Orally dispersible tablet

ABSTRACT

The present invention provides a preparation with improved disintegration property, a preparation showing improved bioavailability of a medicament, production methods thereof and the like. A rapidly disintegrating preparation comprising granules comprising a medicament coated with a coating layer containing sugar or sugar alcohol; and a disintegrant. A production method of a rapidly disintegrating preparation including a step of producing granules comprising a medicament, a step of forming a coating layer containing sugar or sugar alcohol on the obtained granules and a step of mixing the coated granules with a disintegrant and molding the mixture.

TECHNICAL FIELD OF THE INVENTION

The present invention relates to a preparation with improveddisintegration property, a preparation with improved bioavailability ofmedicament, production methods thereof and the like.

BACKGROUND OF THE INVENTION

Patent document 1 discloses a tablet containing sugar alcohol orsaccharide having an average particle size of 30 μm or below, an activeingredient and a disintegrant, and a production method of a tabletcomprising compression molding a mixture containing sugar alcohol orsugar having an average particle size of 30 μm or below, an activeingredient and a disintegrant.

Patent document 2 discloses an orally dispersible solid pharmaceuticalcomposition of agomelatine, which contains agomelatine and granules ofsimultaneously-dried lactose and starch.

Patent document 3 discloses an orally dispersible, coated solidpharmaceutical composition of agomelatine, which contains a central coreor a central layer comprising agomelatine and excipients allowing anorally dispersible formulation to be obtained, and an orally dispersiblecoating.

DOCUMENT LIST Patent Documents

-   patent document 1: WO1997/047287-   patent document 2: JP-A-2005-523253-   patent document 3: JP-A-2007-182440

SUMMARY OF THE INVENTION Exemplary Problems to be Solved by theInvention

An object of the present invention is to provide a preparation capableof promoting medicament absorption from the oral mucosa by rapiddisintegration after sublingual or buccal administration. Suchpreparations have benefits over oral (but not sublingual or buccal)administration of the same medicament, including improvingbioavailability, providing a lower ratio of metabolite to medicament,increasing Cmax, decreasing Tmax, increasing AUC (0-tlqc) and increasingthe coefficient of variance for Cmax and AUC (0-tlqc). Such preparationsalso are useful for treating bipolar disorder generally, as well as theremission and depression phases of the disorder.

Another object of the present invention is to provide a novelformulation technique capable of improving disintegration property. Inaddition, another object of the present invention is to provide apreparation useful as an orally rapidly disintegrating preparation. Suchobjects are not limiting to the invention and are merely exemplary.

Means of Solving the Problems

Formulation: A Rapidly Disintegrating Preparation

The present inventors have conducted intensive studies in an attempt tosolve the aforementioned problems and found that the disintegrationproperty of a medicament can be improved and the bioavailability thereofcan also be improved by containing a component that preventsdisintegration (masking agent, binder and the like) as a granulationcomponent in granules, and formulating the preparation after coating asurface of the granule with sugar or sugar alcohol, which resulted inthe completion of the present invention.

Accordingly, the present invention provides the following.

[1] A rapidly disintegrating preparation comprising granules comprisinga medicament coated with a coating layer containing sugar or sugaralcohol; and a disintegrant (hereinafter sometimes to be abbreviated aspreparation [1], the same for the following [2] to [18], and [37] to[69]).[2] The rapidly disintegrating preparation of the above-mentioned [1],wherein the granules comprising a medicament further contains a binder.[3] The rapidly disintegrating preparation of the above-mentioned [1],wherein the granules comprising a medicament further contains a maskingagent.[4] The rapidly disintegrating preparation of the above-mentioned [1],wherein the granules comprising a medicament further contains asolubilizer.[4-1] The rapidly disintegrating preparation of any of theabove-mentioned [1]-[4], wherein the disintegration time is 15 not morethan 30 sec.[4-2] The rapidly disintegrating preparation of any of theabove-mentioned [1]-[4], wherein the disintegration time is not morethan 30 sec and the absolute hardness is not less than 1.0 N/mm².

The “rapidly disintegrating preparation” of the present invention isalso superior as a preparation for allowing absorption of a medicamentfrom the oral mucosa. Specifically, it is as described below.

[5] The preparation of any of the above-mentioned [1]-[4], which is fororal-mucosal absorption. The terms “oral-mucosal” and “oral-mucosa” inthe context of drug delivery, as used herein connotes administration ofa medicament directly to the mucosal lining of the oral cavity, e.g., bya sublingual or buccal route, such that the medicament enters thesystemic circulation and substantially bypasses hepatic first passmetabolism. The term “oral” in the context of drug delivery, as usedherein connotes administration of a medicament to the oral cavity butnot directly to the mucosa lining the oral cavity. The medicament thatis delivered by the oral route (in contrast to the oral-mucosal route)enters the systemic circulation after absorption in the gastrointestinaltract.[6] The preparation of the above-mentioned [5], wherein the medicamentis(S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide(general name ramelteon; hereinafter sometimes to be abbreviated ascompound A).[7] The preparation of the above-mentioned [5] or [6], which is atablet.[8] A method of producing a rapidly disintegrating preparation,comprising a step of producing granules comprising a medicament,a step of forming a coating layer containing sugar or sugar alcohol onthe obtained granules, anda step of mixing the coated granules with a disintegrant and molding themixture.Formulation: A Preparation for Oral-Mucosal Absorption of Compound A

In addition to the above-mentioned preparation [6], the presentinventors have conducted intensive studies of a preparation superior inthe absorption of compound A from the oral mucosa, and showing improvedbioavailability thereof: [9] A preparation for oral-mucosal absorptioncomprising(S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamideas a medicament; which shows a higher ratio of the medicament in anunchanged form and a metabolite of the medicament (i.e., medicament inunchanged form/metabolite of the medicament) after transfer into bloodthan that by oral administration.

(here and hereinafter, “a metabolite of the medicament” means, inparticular,(2S)-2-hydroxy-N-{2-[(8S)-1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl]ethyl}propanamide,which is known as M-II.)

[10] A preparation for oral-mucosal absorption comprising(S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamideas a medicament; which shows a higher ratio of the medicament in anunchanged form and a metabolite of the medicament after transfer intoblood than that by oral administration, and a disintegration time of notmore than 30 sec.[11] A preparation for oral-mucosal absorption comprising(S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamideas a medicament; which shows a higher ratio of the medicament in anunchanged form and a metabolite to of the medicament after transfer intoblood than that by oral administration, a disintegration time of notmore than 30 sec, and absolute hardness of not less than 1.0 N/mm².[12] A preparation for oral-mucosal absorption comprising(S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamideand a masking agent; which shows not less than about 10-fold improvedbioavailability of(S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide,as compared to that by oral administration.[13] A preparation for oral-mucosal absorption comprising(S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamideand a masking agent; which shows not less than about 10-fold improvedbioavailability of(S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide,as compared to that by oral administration, and a disintegration time ofnot more than 30 sec.[14] A preparation for oral-mucosal absorption comprising(S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamideand a masking agent; which shows not less than about 10-fold improvedbioavailability of(S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide,as compared to that by oral administration, a disintegration time of notmore than 30 sec, and absolute hardness of not less than 1.0 N/mm².[15] A preparation for oral-mucosal absorption comprising(S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide,sugar or sugar alcohol, and a disintegrant; which shows not less thanabout 10-fold improved bioavailability of(S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide,as compared to that by oral administration, and a disintegration time ofnot more than 30 sec.[16] A preparation for oral-mucosal absorption comprising(S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide,sugar or sugar alcohol, and a disintegrant; which shows not less thanabout 10-fold improved bioavailability of(S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide,as compared to that by oral administration, a disintegration time of notmore than 30 sec, and absolute hardness of not less than 1.0 N/mm².[17] The preparation of any of the above-mentioned [9]-[16], which is atablet.[18] The preparation of the above-mentioned [9] or [12], which 20 is inthe form of a film, troche, solution, suspension, freeze-driedpreparation, chewing gum or spray.Method of Use of Compound A: Prophylaxis and/or Treatment of a BipolarDisorder (1)

The present invention also relates to a method of use of compound A forprophylaxis and/or treatment of a bipolar disorder by administering itto a human in need thereof oral-mucosally.

[19] A method for the prophylaxis and/or treatment of a bipolar disordercomprising administering(S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamideoral-mucosally to a human.

(hereinafter sometimes to be abbreviated as method [19], the same forthe following [20] to [23], [28], [34], and [70] to [110]).

[20] The method of the above-mentioned [19], wherein the oral-mucosaladministration is sublingual administration or buccal administration(more preferably sublingual administration).

[21] The method of the above-mentioned [19], wherein(S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamideis administered in 0.05-1.0 mg per day.

[22] The method of the above-mentioned [19], wherein the bipolardisorder is bipolar disorder I.

[23] The method of the above-mentioned [19], wherein the prophylaxisand/or treatment of a bipolar disorder is a treatment of a depressionsymptom associated with the bipolar disorder or maintenance of aremission phase of the bipolar disorder.

[24] A drug for the prophylaxis and/or treatment of a bipolar disorder,which comprises, as an active ingredient,(S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamideto be oral-mucosally administered to a human.

(hereinafter sometimes to be abbreviated as drug [24], the same for thefollowing [25] to [27], and [35]).

[25] The drug of the above-mentioned [24], wherein the oral-mucosaladministration is sublingual administration or buccal administration(more preferably sublingual administration).

[26] The drug of the above-mentioned [24], wherein(S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamideis administered in 0.05-1.0 mg per day.

[27] The drug of the above-mentioned [24], wherein the bipolar disorderis bipolar disorder I.

[28] The method of the above-mentioned [24], wherein the prophylaxisand/or treatment of a bipolar disorder is a treatment of a depressionsymptom associated with the bipolar disorder or maintenance of aremission phase of the bipolar disorder.

[29](S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamidefor the prophylaxis and/or treatment of a bipolar disorder byoral-mucosal administration to a human. (hereinafter sometimes to beabbreviated as compound [29], the same for the following [30] to [33],and [36]).[30] The(S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamideof the above-mentioned [29], wherein the oral-mucosal administration issublingual administration or buccal administration (more preferablysublingual administration).[31] The(S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamideof the above-mentioned [29], which is administered in 0.05-1.0 mg perday.[32] The(S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamideof the above-mentioned [29], wherein the bipolar disorder is bipolardisorder I.[33] The(S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamideof the above-mentioned [29], wherein the prophylaxis and/or treatment ofthe bipolar disorder is a treatment of a depression symptom associatedwith the bipolar disorder or maintenance of a remission phase of thebipolar disorder.[34] The method of the above-mentioned [19]-[23], wherein(S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamideis administered as the preparation of the above-mentioned [5]-[7], or[9]-[18].[35] The drug of the above-mentioned [24]-[28], wherein(S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamideis administered as the preparation of the above-mentioned [5]-[7], or[9]-[18].[36] The(S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamideof the above-mentioned [29]-[33], which is administered as thepreparation of the above-mentioned [5]-[7], or [9]-[18].Formulation: A Preparation for Oral-Mucosal Absorption of Compound A (2)

Another aspect of the present invention relates to the following“formulations with limitation by dose and/or PK profile”.

[37] A preparation for oral-mucosal absorption comprising(S)—N-[2-(1,6,7,6-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide(compound A); wherein (1) the dose of compound A is 0.1 mg a day, and(2) the preparation provides to a human subject in a fasting state Cmaxfor compound A falling within the range of about 0.43 to about 3.13ng/ml and AUC (0-tlqc) for compound A falling within the range of about0.48 to about 2.26 ng·hr/ml.[37-1] A preparation for oral-mucosal absorption comprising(S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide(compound A); wherein (1) the dose of compound A is 0.1 mg a day, (2)the preparation provides to a human subject in a fasting state Cmax forcompound A falling within the range of about 0.43 to about 3.13 ng/mland AUC(0-tlqc) for compound A falling within the range of about 0.48 toabout 2.26 ng·hr/ml, and (3) the average Tmax value of plasma level ofcompound A after administration to a human is not more than about 0.4hrs, preferably, not more than about 0.3 hrs, and more preferably, notmore than about 0.25 hrs.[38] The preparation of the afore-mentioned [37], wherein (1) the doseof compound A is 0.1 mg a day, and (2) the preparation provides to ahuman subject in a fasting state Cmax for compound A falling within therange of about 0.66 to about 2.05 ng/ml and AUC (0-tlqc) for compound Afalling within the range of about 0.67 to about 1.62 ng·hr/ml.[38-1] The preparation of the afore-mentioned [37-1], wherein (1) thedose of compound A is 0.1 mg a day, (2) the preparation provides to ahuman subject in a fasting state Cmax for compound A falling within therange of about 0.66 to about 2.05 ng/ml and AUC (0-tlqc) for compound Afalling within the range of about 0.67 to about 1.62 ng·hr/ml, and (3)the average Tmax value of plasma level of compound A afteradministration to a human is not more than about 0.4 hrs, preferably,not more than about 0.3 hrs, and more preferably, not more than about0.25 hrs.[39] A preparation for oral-mucosal absorption comprising(S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide(compound A); wherein (1) the dose of compound A is 0.4 mg a day, and(2) the preparation provides to a human subject in a fasting state Cmaxfor compound A falling within the range of about 2.04 to about 6.89ng/ml and AUC (0-tlqc) for compound A falling within the range of about1.52 to about 6.68 ng·hr/ml.[39-1] A preparation for oral-mucosal absorption comprising(S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide(compound A); wherein (1) the dose of compound A is 0.4 mg a day, (2)the preparation provides to a human subject in a fasting state Cmax forcompound A falling within the range of about 2.04 to about 6.89 ng/mland AUC(0-tlqc) for compound A falling within the range of about 1.52 toabout 6.68 ng·hr/ml, and (3) the average Tmax value of plasma level ofcompound A after administration to a human is not more than about 0.4hrs, preferably, not more than about 0.3 hrs, and more preferably, notmore than about 0.25 hrs.[40] The preparation of the afore-mentioned [39], wherein (1) the doseof compound A is 0.4 mg a day, and (2) the preparation provides to ahuman subject in a fasting state Cmax for compound A falling within therange of about 2.54 to about 5.54 ng/ml and AUC (0-tlqc) for compound Afalling within the range of about 1.98 to about 5.12 ng·hr/ml.[40-1] The preparation of the afore-mentioned [39-1], wherein (1) thedose of compound A is 0.4 mg a day, (2) the preparation provides to ahuman subject in a fasting state Cmax for compound A falling within therange of about 2.54 to about 5.54 ng/ml and AUC (0-tlqc) for compound Afalling within the range of about 1.98 to about 5.12 ng·hr/ml, and (3)the average Tmax value of plasma level of(S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamideafter administration to a human is not more than about 0.4 hrs,preferably, not more than about 0.3 hrs, and more preferably, not morethan about 0.25 hrs.[41] A preparation for oral-mucosal absorption comprising(S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide(compound A); wherein (1) the dose of compound A is 0.8 mg a day, and(2) the preparation provides to a human subject in a fasting state Cmaxfor compound A falling within the range of about 3.63 to about 14.06ng/ml and AUC (0-tlqc) for compound A falling within the range of about2.48 to about 14.43 ng·hr/ml.[41-1] A preparation for oral-mucosal absorption comprising(S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide(compound A); wherein (1) the dose of compound A is 0.8 mg a day, (2)the preparation provides to a human subject in a fasting state Cmax forcompound A falling within the range of about 3.63 to about 14.06 ng/mland AUC (0-tlqc) for compound A falling within the range of about 2.48to about 14.43 ng·hr/ml, and (3) the average Tmax value of plasma levelof(S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamideafter administration to a human is not more than about 0.4 hrs,preferably, not more than about 0.3 hrs, and more preferably, not morethan about 0.25 hrs.[42] The preparation of the afore-mentioned [41], wherein (1) the doseof compound A is 0.8 mg a day, and (2) the preparation provides to ahuman subject in a fasting state Cmax for compound A falling within therange of about 4.85 to about 10.54 ng/ml and AUC (0-tlqc) for compound Afalling within the range of about 3.60 to about 9.91 ng·hr/ml.[42-1] The preparation of the afore-mentioned [41-1], wherein (1) thedose of compound A is 0.8 mg a day, (2) the preparation provides to ahuman subject in a fasting state Cmax for compound A falling within therange of about 4.85 to about 10.54 ng/ml and AUC (0-tlqc) for compound Afalling within the range of about 3.60 to about 9.91 ng·hr/ml, and (3)the average Tmax value of plasma level of(S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamideafter administration to a human is not more than about 0.4 hrs,preferably, not more than about 0.3 hrs, and more preferably, not morethan about 0.25 hrs.[43] A preparation for oral-mucosal absorption comprising(S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide(compound A); wherein (1) the dose of compound A is 0.05-1.0 mg a day;and (2) the AUC ratio of the metabolite of compound A (M-II) to compoundA in an unchanged form after administration to a human is not more thanabout 20.[44] A preparation for oral-mucosal absorption comprising(S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide(compound A); wherein (1) the dose of compound A is 0.1-0.8 mg a day;and (2) the AUC ratio of the metabolite of compound A (M-II) to compoundA in an unchanged form after administration to a human is not more thanabout 20.[45] The preparation for oral-mucosal absorption of the afore-mentioned[43], wherein the AUC ratio is not more than about 10.[46] The preparation for oral-mucosal absorption of the afore-mentioned[44], wherein the AUC ratio is not more than about 10.[47] A preparation for oral-mucosal absorption comprising(S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide;wherein the AUC ratio of(S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamidein an unchanged form to a metabolite of(S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide(M-II) after administration to a human is not less than about 5-foldthan that by oral administration.[48] The preparation for oral-mucosal absorption of the afore-mentioned[47], wherein the AUC ratio is not less than about 10-fold than that byoral administration.[49] The preparation for oral-mucosal absorption of any of theafore-mentioned [47] or [48], wherein the AUC ratio is not more thanabout 30-fold, preferably, not more than about 20-fold.[50] A preparation for oral-mucosal absorption comprising(S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide;wherein the AUC ratio of the metabolite of(S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide(M-II) to(S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamidein an unchanged form after administration to a human is not more thanabout 20.[51] The preparation for oral-mucosal absorption of afore-mentioned[50], wherein the AUC ratio is not more than about 10, more preferably,not more than about 5.[52] A preparation for oral-mucosal absorption comprising(S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-h]furan-8-yl)ethyl]propionamide;wherein the bioavailability of(S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamideis improved not less than about 10-fold than that by oraladministration, more specifically, is improved within the range from notless than about 10-fold to not more than about 30-fold than that by oraladministration.[53] A preparation for oral-mucosal absorption comprising(S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide,wherein the average Tmax value of plasma level of(S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamideafter administration to a human is not more than about 0.4 hrs,preferably, not more than about 0.3 hrs, and more preferably, not morethan about 0.25 hrs.[54] The preparation for oral-mucosal absorption of any of theafore-mentioned [47] to [52], wherein the average Tmax value of plasmalevel of(S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamideafter administration to a human is not more than about 0.4 hrs,preferably, not more than about 0.3 hrs, more preferably, not more thanabout 0.25 hrs.[55] A preparation for oral-mucosal absorption comprising(S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide,wherein the coefficient of variation (CV) of pharmacokinetic parametersincluding Cmax and AUC of(S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamideafter administration to a human is not more than about 45%, preferably,not more than about 35%, and more preferably, not more than about 30%.[56] The preparation for oral-mucosal absorption of any of theafore-mentioned [47] to [54], wherein the coefficient of variation (CV)of pharmacokinetic parameters including Cmax and AUC of(S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamideafter administration to a human is not more than about 45%, preferably,not more than about 35%, and more preferably, not more than about 30%.[57] A preparation for oral-mucosal absorption comprising(S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide;wherein the dose of(S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamideis 0.05-1.0 mg a day.[58] The preparation for oral-mucosal absorption of the afore-mentioned[57], wherein the dose of(S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamideis 0.1-0.8 mg a day.[59] The preparation for oral-mucosal absorption of any of theafore-mentioned [57] or [58], wherein the AUC ratio of(S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamidein an unchanged form to a metabolite of(S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide(M-II) after administration to a human is not less than about 5-foldthan that by oral administration.[60] The preparation for oral-mucosal absorption of the afore-mentioned[59], wherein the AUC ratio is not less than about 10-fold than that byoral administration.[61] The preparation for oral-mucosal absorption of the afore-mentioned[60], wherein the AUC ratio is not less than about 10-fold than that byoral administration.[62] The preparation for oral-mucosal absorption of any of theafore-mentioned [59] to [61], wherein the AUC ratio is not more thanabout 30-fold, preferably, not more than about 20-fold.[63] The preparation for oral-mucosal absorption of afore-mentioned [57]or [58], wherein the AUC ratio of the metabolite of(S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide(M-II) to(S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamidein an unchanged form after administration to a human is not more thanabout 20.[64] The preparation for oral-mucosal absorption of the afore-somentioned [63], wherein the AUC ratio is not more than about 10.[65] The preparation for oral-mucosal absorption of any of theafore-mentioned [63] or [64], wherein the AUC ratio is not less thanabout 5.[66] The preparation for oral-mucosal absorption of afore-mentioned [57]or [58], wherein the bioavailability of(S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamideis improved not less than about 10-fold than that by oraladministration, more specifically, is improved within the range from notless than about 10-fold to not more than about 30-fold than that by oraladministration.[67] The preparation for oral-mucosal absorption of any of theafore-mentioned [57] to [66], wherein the average Tmax value of plasmalevel of(S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamideafter administration to a human is not more than about 0.4 hrs,preferably, not more than about 0.3 hrs, and more preferably, not morethan about 0.25 hrs.[68] The preparation for oral-mucosal absorption of any of theafore-mentioned [57] to [67], wherein the coefficient of variation (CV)of pharmacokinetic parameters including Cmax and AUC of(S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamideafter administration to a human is not more than about 45%, preferably,not more than about 35%, and more preferably, not more than about 30%.[69] The preparation for oral-mucosal absorption of any of theafore-mentioned [57] to [68], wherein the preparation further contains adisintegrant.Method of Use of Compound A: Prophylaxis and/or Treatment of a BipolarDisorder (2)

Another aspect of the present invention relates to the following “methodof use of compound A with limitation by dose and/or PK profile”.

[70] A method for the prophylaxis and/or treatment of a bipolar disordercomprising administering daily 0.05 to 1.0 mg of(S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamideto the oral mucosa of a human in need thereof.

[71] The method of the afore-mentioned [70], wherein 0.1 to 0.8 mg of(S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamideis administered daily.

[72] The method of any of the afore-mentioned [70] or [71], wherein(S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamideis administered by a sublingual route of administration or a buccalroute of administration.

[73] A method for the prophylaxis and/or treatment of a bipolar disordercomprising administering daily 0.1 mg of(S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide(compound A) to the oral mucosa of a human in need thereof, wherein inthe fasting state, Cmax for compound A falls within the range of about0.43 to about 3.13 ng/ml and AUC (0-tlqc) for compound A falls withinthe range of about 0.48 to about 2.26 ng·hr/ml.[73-1] A method for the prophylaxis and/or treatment of a bipolardisorder comprising administering daily 0.1 mg of(S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide(compound A) to the oral mucosa of a human in need thereof, wherein inthe fasting state, Cmax for compound A falls within the range of about0.43 to about 3.13 ng/ml and AUC (0-tlqc) for compound A falls withinthe range of about 0.48 to about 2.26 ng·hr/ml; and the average Tmaxvalue of plasma level of compound A after administration to a human isnot more than about 0.4 hrs, preferably, not more than about 0.3 hrs,and more preferably, not more than about 0.25 hrs.[74] The method of any of the afore-mentioned [73] or [73-1], whereinthe oral-mucosal administration is sublingual administration or buccaladministration.[75] The method of any of the afore-mentioned [73] or [73-1], whereinthe bipolar disorder is bipolar disorder I.[76] The method of any of the afore-mentioned [73] or [73-1], whereinthe prophylaxis and/or treatment of a bipolar disorder is a treatment ofa depression symptom associated with the bipolar disorder or maintenanceof a remission phase of the bipolar disorder.[77] The method of any of the afore-mentioned [73] or [73-1], wherein inthe fasting state, Cmax for compound A falls within the range of about0.66 to about 2.05 ng/ml and AUC (0-tlqc) for compound A falls withinthe range of about 0.67 to about 1.62 ng·hr/ml.[78] The method of the afore-mentioned [77], wherein the oral-mucosaladministration is sublingual administration or buccal administration.[79] The method of the afore-mentioned [77], wherein the bipolardisorder is bipolar disorder I.[80] The method of the afore-mentioned [77], wherein the prophylaxisand/or treatment of a bipolar disorder is a treatment of a depressionsymptom associated with the bipolar disorder or maintenance of aremission phase of the bipolar disorder.[81] A method for the prophylaxis and/or treatment of a bipolar disordercomprising administering daily 0.4 mg of(S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide(compound A) to the oral mucosa of a human in need thereof, wherein inthe fasting state, Cmax for compound A falls within the range of about2.04 to about 6.89 ng/ml and AUC (0-tlqc) for compound A falls withinthe range of about 1.52 to about 6.68 ng·hr/ml.[81-1] A method for the prophylaxis and/or treatment of a bipolardisorder comprising administering daily 0.4 mg of(S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide(compound A) to the oral mucosa of a human in need thereof, wherein inthe fasting state, Cmax for compound A falls within the range of about2.04 to about 6.89 ng/ml and AUC (0-tlqc) for compound A falls withinthe range of about 1.52 to about 6.68 ng·hr/ml; and the average Tmaxvalue of plasma level of compound A after administration to a human isnot more than about 0.4 hrs, preferably, not more than about 0.3 hrs,and more preferably, not more than about 0.25 hrs.[82] The method of any of the afore-mentioned [81] or {81-1}, whereinthe oral-mucosal administration is sublingual administration or buccaladministration.[83] The method of the afore-mentioned [82] wherein the bipolar disorderis bipolar disorder I.[84] The method of the afore-mentioned [82], wherein the prophylaxisand/or treatment of a bipolar disorder is a treatment of a depressionsymptom associated with the bipolar disorder or maintenance of aremission phase of the bipolar disorder.[85] The method of any of the afore-mentioned [81] or [81-1], wherein inthe fasting state, Cmax for compound A falls within the range of about2.54 to about 5.54 ng/ml and AUC (0-tlqc) for compound A falls withinthe range of about 1.98 to about 5.12 ng·hr/ml.[86] The method of the afore-mentioned [85], wherein the oral-mucosaladministration is sublingual administration or buccal administration.[87] The method of the afore-mentioned [85], wherein the bipolardisorder is bipolar disorder I.[88] The method of the afore-mentioned [85], wherein the prophylaxisand/or treatment of a bipolar disorder is a treatment of a depressionsymptom associated with the bipolar disorder or maintenance of aremission phase of the bipolar disorder.[89] A method for the prophylaxis and/or treatment of a bipolar disordercomprising administering daily 0.8 mg of(S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-h]furan-8-yl)ethyl]propionamide(compound A) to the oral mucosa of a human in need thereof, wherein inthe fasting state, Cmax for compound A falls within the range of about3.63 to about 14.06 ng/ml and AUC (0-tlqc) for compound A falls withinthe range of about 2.48 to about 14.43 ng·hr/ml.[89-1] A method for the prophylaxis and/or treatment of a bipolardisorder comprising administering daily 0.8 mg of(S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide(compound A) to the oral mucosa of a human in need thereof, wherein inthe fasting state, Cmax for compound A falls within the range of about3.63 to about 14.06 ng/ml and AUC (0-tlqc) for compound A falls withinthe range of about 2.48 to about 14.43 ng·hr/ml; and the average Tmaxvalue of plasma level of compound A after administration to a human isnot more than about 0.4 hrs, preferably, not more than about 0.3 hrs,and more preferably, not more than about 0.25 hrs.[90] The method of any of the afore-mentioned [89] or [89-1], whereinthe oral-mucosal administration is sublingual administration or buccaladministration.[91] The method of the afore-mentioned [90], wherein the bipolardisorder is bipolar disorder I.[92] The method of the afore-mentioned [90], wherein the prophylaxisand/or treatment of a bipolar disorder is a treatment of a depressionsymptom associated with the bipolar disorder or maintenance of aremission phase of the bipolar disorder.[93] The method of any of the afore-mentioned [89] or [89-1], wherein inthe fasting state, Cmax for compound A falls within the range of about4.85 to about 10.54 ng/ml and AUC (0-tlqc) for compound A falls withinthe range of 3.60 to about 9.91 ng·hr/ml.[94] The method of the afore-mentioned [93], wherein the oral-mucosaladministration is sublingual administration or buccal administration.[95] The method of the afore-mentioned [93], wherein the bipolardisorder is bipolar disorder I.[96] The method of the afore-mentioned [93], wherein the prophylaxisand/or treatment of a bipolar disorder is a treatment of a depressionsymptom associated with the bipolar disorder or maintenance of aremission phase of the bipolar disorder.[97] A method for the prophylaxis and/or treatment of a bipolar disordercomprising administering daily 0.05 to 1.0 mg of(S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide(compound A) to the oral mucosa of a human in need thereof, wherein theAUC ratio of a metabolite of compound A (M-II) to compound A in anunchanged form after administration is not more than 20.[98] A method for the prophylaxis and/or treatment of a bipolar disordercomprising administering daily 0.1 to 0.8 mg of(S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide(compound A) to the oral mucosa of a human in need thereof, wherein theAUC ratio of a metabolite of compound A (M-II) to compound A in anunchanged form after administration is not more than 20.[99] The method of afore-mentioned [97], wherein the AUC ratio is notmore than 10.[100] The method of afore-mentioned [98], wherein the AUC ratio is notmore than 10.[101.] The method of any of afore-mentioned [70] to [72], wherein theAUC ratio of(S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamidein an unchanged form, to a metabolite of(S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide(M-II) after administration is not less than about 5-fold than that byoral administration.[102] The method of any of the afore-mentioned [101], wherein the AUCratio is not less than about 10-fold than that by oral administration.[103] The method of any of the afore-mentioned [102], wherein the AUCratio is not more than about 30-fold, preferably, not more than about20-fold.[104] The method of any of afore-mentioned [70] to [72], wherein the AUCratio of a metabolite of(S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide(M-II) to(S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamidein an unchanged form after administration is not more than about 20.[105] The method of afore-mentioned [104], wherein the AUC ratio is notmore than about 10, more preferably, not more than about 5.[106] The method of any of the afore-mentioned [70] to [72], wherein(S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamideis administered so that the bioavailability of(S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamideis improved not less than about 10-fold than that by oraladministration, more specifically, is improved within the range from notless than about 10-fold to not more than about 30-fold than that by oraladministration.[107] The method of any of afore-mentioned [70] to [72], and to [106],wherein(S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamideis administered so that the average Tmax value of plasma level of(S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamideafter administration is not more than about 0.4 hrs, preferably, notmore than about 0.3 hrs, and more preferably, not more than about 0.25hrs.[108] The method of any of afore-mentioned [70] to [72], and [101] to[107], wherein(S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamideis administered so that the coefficient of variation (CV) ofpharmacokinetic parameters including Cmax and AUC of(S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamideafter administration is not more than about 45%, preferably, not morethan about 35%, and more preferably, not more than about 30%.[109] The method of any of the above-mentioned [70] to [72] and [101] to108], wherein the bipolar disorder is bipolar disorder I.[110] The method of the above-mentioned [109], wherein the prophylaxisand/or treatment of a bipolar disorder is a treatment of a depressionsymptom associated with the bipolar disorder or maintenance of aremission phase of the bipolar disorder.[111] A drug for the prophylaxis and/or treatment of a bipolar disordercomprising daily 0.1 mg of(S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide(compound A) to be administered to the oral mucosa of a human in needthereof, wherein in the fasting state, Cmax for compound A falls withinthe range of about 0.43 to about 3.13 ng/ml and AUC (0-tlqc) forcompound A falls within the range of about 0.48 to about 2.26 ng·hr/ml.[112] The drug of the above-mentioned [111], wherein the oral-mucosaladministration is sublingual administration or buccal administration.[113] The drug of any of the above-mentioned [111] and [112], whereinthe bipolar disorder is bipolar disorder I.[114] The drug of any of the above-mentioned [111] to [113], wherein theprophylaxis and/or treatment of a bipolar disorder is a treatment of adepression symptom associated with the bipolar disorder or maintenanceof a remission phase of the bipolar disorder.[115] The drug of the above-mentioned [111], wherein in the fastingstate, Cmax for compound A falls within the range of about 0.66 to about2.05 ng/ml and AUC (0-tlqc) for compound A falls within the range ofabout 0.67 to about 1.62 ng·hr/ml.[116] The drug of the above-mentioned [115], wherein the oral-mucosaladministration is sublingual administration or buccal administration.[117] The drug of any of the above-mentioned [115] and [116], whereinthe bipolar disorder is bipolar disorder I.[118] The drug of any of the above-mentioned [115] to [117], wherein theprophylaxis and/or treatment of a bipolar disorder is a treatment of adepression symptom associated with the bipolar disorder or maintenanceof a remission phase of the bipolar disorder.[119] A drug for the prophylaxis and/or treatment of a bipolar disordercomprising daily 0.4 mg of(S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide(compound A) to be administered to the oral mucosa of a human in needthereof, wherein in the fasting state, Cmax for compound A falls withinthe range of about 2.04 to about 6.89 ng/ml and AUC (0-tlqc) forcompound A falls within the range of about 1.52 to about 6.68 ng·hr/ml.[120] The drug of the above-mentioned [119], wherein the oral-mucosaladministration is sublingual administration or buccal administration.[121] The drug of any of the above-mentioned [119] and [120], whereinthe bipolar disorder is bipolar disorder I.[122] The drug of any of the above-mentioned [119] to [121], wherein theprophylaxis and/or treatment of a bipolar disorder is a treatment of adepression symptom associated with the bipolar disorder or maintenanceof a remission phase of the bipolar disorder.[123] The drug of the above-mentioned [119], wherein in the fastingstate, Cmax for compound A falls within the range of about 2.54 to about5.54 ng/ml and AUC (0-tlqc) for compound A falls within the range ofabout 1.98 to about 5.12 ng·hr/ml.[124] The drug of the above-mentioned [123], wherein the oral-mucosaladministration is sublingual administration or buccal administration.[125] The drug of any of the above-mentioned [123] and [124], whereinthe bipolar disorder is bipolar disorder I.[126] The drug of any of the above-mentioned [123] to [125], wherein theprophylaxis and/or treatment of a bipolar disorder is a treatment of adepression symptom associated with the bipolar disorder or maintenanceof a remission phase of the bipolar disorder.[127] A drug for the prophylaxis and/or treatment of a bipolar disordercomprising daily 0.8 mg of(S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide(compound A) to be administered to the oral mucosa of a human in needthereof, wherein in the fasting state, Cmax for compound A falls withinthe range of about 3.63 to about 14.06 ng/ml and AUC (0-tlqc) forcompound A falls within the range of about 2.48 to about 14.43 ng·hr/ml.[128] The drug of the above-mentioned [127], wherein the oral-mucosaladministration is sublingual administration or buccal administration.[129] The drug of any of the above-mentioned [127] and [128], whereinthe bipolar disorder is bipolar disorder I.[130] The drug of any of the above-mentioned [127] to [129], wherein theprophylaxis and/or treatment of a bipolar disorder is a treatment of adepression symptom associated with the bipolar disorder or maintenanceof a remission phase of the bipolar disorder.[131] The drug of the above-mentioned [127], wherein in the fastingstate, Cmax for compound A falls within the range of about 4.85 to about10.54 ng/ml and AUC (0-tlqc) for compound A falls within the range of3.60 to about 9.91 ng·hr/ml.[132] The drug of the above-mentioned [131], wherein the oral-mucosaladministration is sublingual administration or buccal administration.[133] The drug of any of the above-mentioned [131] and [132], whereinthe bipolar disorder is bipolar disorder I.[134] The drug of any of the above-mentioned [131] to [133], wherein theprophylaxis and/or treatment of a bipolar disorder is a treatment of adepression symptom associated with the bipolar disorder or maintenanceof a remission phase of the bipolar disorder.[135](S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide(compound A) for the prophylaxis and/or treatment of a bipolar disorder,wherein 1) daily 0.1 mg of compound A is administered to the oral mucosaof a human in need thereof, and 2) in the fasting state, Cmax forcompound A falls within the range of about 0.43 to about 3.13 ng/ml andAUC (0-tlqc) for compound A falls within the range of about 0.48 toabout 2.26 ng·hr/ml.[136] The(S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide(compound A) of the above-mentioned wherein the oral-mucosaladministration is sublingual administration or buccal administration.[137] The(S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide(compound A) of any of the above-mentioned [135] and [136], wherein thebipolar disorder is bipolar disorder I.[138] The(S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide(compound A) of any of the above-mentioned [135] to [137], wherein theprophylaxis and/or treatment of a bipolar disorder is a treatment of adepression symptom associated with the bipolar disorder or maintenanceof a remission phase of the bipolar disorder.[139] The(S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide(compound A) of the above-mentioned wherein in the fasting state, Cmaxfor compound A falls within the range of about 0.66 to about 2.05 ng/mland AUC (0-tlqc) for compound A falls within the range of about 0.67 toabout 1.62 ng·hr/ml.[140] The(S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide(compound A) of the above-mentioned [139], wherein the oral-mucosaladministration is sublingual administration or buccal administration.[141] The(S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide(compound A) of any of the above-mentioned [139] and [140], wherein thebipolar disorder is so bipolar disorder I.[142] The(S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide(compound A) of any of the above-mentioned [139] to [141], wherein theprophylaxis and/or treatment of a bipolar disorder is a treatment of adepression symptom associated with the bipolar disorder or maintenanceof a remission phase of the bipolar disorder.[143](S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide(compound A) for the prophylaxis and/or treatment of a bipolar disorder,wherein 1) daily 0.4 mg of compound A is administered to the oral mucosaof a human in need thereof, and 2) in the fasting state, Cmax forcompound A falls within the range of about 2.04 to about 6.89 ng/ml andAUC (0-tlqc) for compound A falls within the range of about 1.52 toabout 6.68 ng·hr/ml.[144] The(S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide(compound A) of the above-mentioned [143], wherein the oral-mucosaladministration is sublingual administration or buccal administration.[145] The(S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide(compound A) of any of the above-mentioned [143] and [144], wherein thebipolar disorder is bipolar disorder I.[146] The(S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide(compound A) of any of the above-mentioned [143] to [145], wherein theprophylaxis and/or treatment of a bipolar disorder is a treatment of adepression symptom associated with the bipolar disorder or maintenanceof a remission phase of the bipolar disorder.[147] The(S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide(compound A) of the above-mentioned [143], wherein in the fasting state,Cmax for compound A falls within the range of about 2.54 to about 5.54ng/ml and AUC (0-tlqc) for compound A falls within the range of about1.98 to about 5.12 ng·hr/ml.[148] The(S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide(compound A) of the above-mentioned [147], wherein the oral-mucosaladministration is sublingual administration or buccal administration.[149] The(S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide(compound A) of any of the above-mentioned [147] and [148], wherein thebipolar disorder is bipolar disorder I.[150] The(S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide(compound A) of any of the above-mentioned [147] to [149], wherein theprophylaxis and/or treatment of a bipolar disorder is a treatment of adepression symptom associated with the bipolar disorder or maintenanceof a remission phase of the bipolar disorder.[151](S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide(compound A) for the prophylaxis and/or treatment of a bipolar disorder,wherein 1) daily 0.8 mg of compound A is administered to the oral mucosaof a human in need thereof, and 2) in the fasting state, Cmax forcompound A falls within the range of about 3.63 to about 14.06 ng/ml andAUC (0-tlqc) for compound A falls within the range of about 2.48 toabout 14.43 ng·hr/ml.[152] The(S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide(compound A) of the above-mentioned [151], wherein the oral-mucosaladministration is sublingual administration or buccal administration.[153] The(S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide(compound A) of any of the above-mentioned [151] and [152], wherein thebipolar disorder is bipolar disorder I.[154] The(S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide(compound A) of any of the above-mentioned [151] to [153], wherein theprophylaxis and/or treatment of a bipolar disorder is a treatment of adepression symptom associated with the bipolar disorder or maintenanceof a remission phase of the bipolar disorder.[155] The(S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide(compound A) of the above-mentioned [151], wherein in the fasting state,Cmax for compound A falls within the range of about 4.85 to about 10.54ng/ml and AUC (0-tlqc) for compound A falls within the range of 3.60 toabout 9.91 ng·hr/ml.[156] The(S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide(compound A) of the above-mentioned [155], wherein the oral-mucosaladministration is sublingual administration or buccal administration.[157] The(S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide(compound A) of any of the above-mentioned [155] and [156], wherein thebipolar disorder is bipolar disorder T.[158] The(S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide(compound A) of any of the above-mentioned [155] to [157], wherein theprophylaxis and/or treatment of a bipolar disorder is a treatment of adepression symptom associated with the bipolar disorder or maintenanceof a remission phase of the bipolar disorder.

DETAILED DESCRIPTION OF THE INVENTION

Effect of the Invention

According to the present invention, a rapidly disintegrating preparationsuperior in the disintegration property, a preparation with improvedmedicament bioavailability and production methods thereof and the likecan be provided.

The rapidly disintegrating preparations [1] to [7] of the presentinvention contain a medicament in granules, and a disintegrant as anextragranule component. Even when a medicament (e.g., compound A etc.)with poor compatibility with the disintegrant is to be used, therefore,an influence of the disintegrant on the medicament can be reduced, thusimproving the stability of the medicament.

The rapidly disintegrating preparation of the present invention canimprove disintegration property by enclosing a component that preventsdisintegration (e.g., masking agent, binder etc.) in granules. Inaddition, it can achieve high disintegration property by ensuring theinvasion route of water into the preparation by coating the componentthat prevents disintegration with sugar or sugar alcohol. Moreover, inthe rapidly disintegrating preparation of the present invention, amedicament is coated with sugar or sugar alcohol. Therefore, thedissolution property of the medicament from the preparation can beimproved even when the medicament has high surface hydrophobicity, byaltering the surface to be hydrophilic.

The rapidly disintegrating preparation of the present invention canachieve both the good disintegration property and the good preparationhardness.

Among the rapidly disintegrating preparations [1] to [7] of the presentinvention, the rapidly disintegrating preparations [5] to [7] fororal-mucosal absorption of the present invention are expected to providean immediate effect by absorption of the medicament from the oralmucosa.

The rapidly disintegrating preparation for oral-mucosal absorption ofthe present invention can improve bioavailability by increasing theblood concentration of a medicament (e.g., compound A etc.) susceptibleto a first pass effect by oral administration. In addition, the rapidlydisintegrating preparation for oral-mucosal absorption of the presentinvention can suppress inconsistent absorption of such medicaments, andfurther, inconsistent effectiveness as medicaments. Moreover, therapidly disintegrating preparation for oral-mucosal absorption of thepresent invention can afford a low dose medicament and a compactpreparation based on the improved medicament bioavailability.

According to the production method of the present invention, the rapidlydisintegrating preparations [1] to [7] of the present invention havingthe above-mentioned effects can be produced.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 demonstrates the mean serum concentration of compound A afteroral-mucosal delivery at different concentrations.

FIG. 2 demonstrates the mean serum concentration of compound A afteroral-mucosal delivery compared to the concentration of compound A afteroral delivery.

FIG. 3 demonstrates the mean serum concentration of metabolite M-IIafter oral-mucosal delivery at different concentrations.

FIG. 4 demonstrates the mean serum concentration of metabolite M-IIafter oral-mucosal delivery compared to the concentration of M-II afteroral delivery.

DESCRIPTION OF EMBODIMENTS

Formulation: A Rapidly Disintegrating Preparation

The rapidly disintegrating preparation of the present invention isexplained in detail in the following.

The rapidly disintegrating preparation of the present invention containsgranules comprising a medicament coated with a coating layer containingsugar or sugar alcohol, and a disintegrant.

While the medicament to be used in the present invention is notparticularly limited, for example, antipyretic analgesic antiphlogisticdrugs, antipsychotic drugs, antianxiety drugs, antidepressant drugs,sedative-hypnotic drugs, gastrointestinal drugs, antacid drugs,antitussive expectorant drugs, antihypertensive agents, drugs fordiabetes, drugs for osteoporosis, skeleton muscle relaxants, anti-canceragents and the like can be used.

In the rapidly disintegrating preparation of the present invention, thecontent of the medicament is generally 0.03-50 wt %, preferably 0.03-20wt %, more preferably 0.03-3 wt %, relative to the total weight of thepreparation.

The rapidly disintegrating preparation of the present invention containsa disintegrant as an extragranule component, and therefore, an influenceof the disintegrant on the medicament can be reduced even when amedicament having poor compatibility with the disintegrant is used, andthe medicament stability can be improved. Thus, the present invention isparticularly effective when a medicament having poor compatibility withthe disintegrant (e.g. compound A, etc) is used as a medicament.

Compound A is a known therapeutic agent for sleep disorders, which isdisclosed in U.S. Pat. No. 6,034,239 and the like, and can be producedby a known method such as the method described in this document and thelike.

In the rapidly disintegrating preparation of the present invention, anexcipient is contained in granules comprising a medicament coated with acoating layer containing sugar or sugar alcohol.

Examples of the excipient include starches such as corn starch and thelike; sugar or sugar alcohols such as lactose, fructose, glucose,mannitol (e.g., D-mannitol), sorbitol (e.g., D-sorbitol), erythritol(e.g., D-erythritol), sucrose and the like: anhydrous calcium phosphate,microcrystalline cellulose, micromicrocrystalline cellulose, powderedglycyrrhiza, sodium hydrogen carbonate, calcium phosphate, calciumsulfate, calcium carbonate, precipitated calcium carbonate, calciumsilicate and the like, and corn starch, D-mannitol and microcrystallinecellulose are preferable.

The content of the excipient is generally 13-94 wt %, preferably 54-94wt %, more preferably 81-93 wt %, relative to the total weight of thepreparation.

The rapidly disintegrating preparation of the present invention mayfurther contain an additive, where necessary, in the granules comprisinga medicament.

Examples of the additive optionally contained in the granules comprisinga medicament include binder, masking agent, solubilizer and the like,which may be used in combination where necessary.

Examples of the binder include starches such as potato starch, wheatstarch, rice starch, partly pregelatinized starch, pregelatinizedstarch, porous starch and the like, hydroxypropylcellulose,hydroxypropylmethylcellulose, polyvinylpyrrolidone, gelatin, starch, gumarabic powder, tragacanth, carmellose, sodium alginate, pullulan,glycerol and the like, and partly pregelatinized starch,hydroxypropylcellulose and pregelatinized starch are preferable.

The content of the binder is generally 0.5-20 wt %, preferably 0.5-15 wt%, more preferably 1-10 wt %, relative to the total weight of thepreparation.

Examples of the masking agent include various flavoring agents(thaumatin, sucralose, saccharin, aspartame, xylitol, citric acid,L-sodium glutamate etc.), various receptor antagonists (BENECOAT, sodiumchloride etc.), various cation channel antagonists (L-arginine etc.),various clathration agents (α-cyclodextrin, β-cyclodextrin etc.),various flavors (strawberry flavor, mint flavor, orange flavor, vanillinetc.) and the like. Two or more thereof may be used in combination wherenecessary.

The content of the masking agent is generally 0.01-10 wt %, preferably0.01-5 wt %, more preferably 0.01-1 wt %, relative to the total weightof the preparation.

Examples of the solubilizer include various aqueous solvents(polyethylene glycol, propylene glycol, glycerol etc.), variousclathration agents (α-cyclodextrin, β-cyclodextrin etc.), varioussurfactants (sodium lauryl sulfate, polysorbate 80,polyoxyethylene(160)polyoxypropylene(30)glycol etc.) and the like. Twoor more thereof may be used in combination where necessary.

The content of the solubilizer is generally not more than 20 wt %,preferably not more than 15 wt %, more preferably not more than 10 wt %,relative to the total weight of the preparation.

In the rapidly disintegrating preparation of the present invention,disintegration property can be improved by including a component thatprevents disintegration (e.g., masking agent, binder, solubilizer etc.)in granules. In addition, as mentioned below, the preparation canachieve high disintegration property by ensuring the invasion route ofwater into the preparation by coating the component that preventsdisintegration with sugar or sugar alcohol.

The rapidly disintegrating preparation of the present invention containssugar or sugar alcohol in a coating layer formed on the granulescomprising a medicament.

Examples of the sugar or sugar alcohol include lactose, fructose,glucose, mannitol (e.g., D-mannitol), sorbitol (e.g., D-sorbitol),erythritol (e.g., D-erythritol), sucrose and the like, and D-mannitol ispreferable.

The preparation can achieve high disintegration property by ensuring theinvasion route of water into the preparation by coating the granulescomprising a medicament with sugar or sugar alcohol. In addition, thedissolution property of the medicament from the preparation can beimproved.

The content of the sugar contained in the coating layer is generally5-20 wt %, preferably 5-15 wt %, more preferably 5-10 wt %, relative tothe total weight of the preparation.

The content of the sugar alcohol contained in the coating layer isgenerally 5-20 wt %, preferably 5-15 wt %, more preferably 5-10 wt %,relative to the total weight of the preparation.

The content of the sugar and sugar alcohol contained in the coatinglayer is generally 5-20 wt %, preferably 5-15 wt %, more preferably 5-10wt %, relative to the total weight of the preparation.

The rapidly disintegrating preparation of the present invention mayfurther contain an additive in the coating layer as necessary.

Examples of the additive optionally contained in the coating layerinclude excipient, disintegrant and the like, which may be used incombination as necessary.

Examples of the excipient include starches such as corn starch and thelike; anhydrous calcium phosphate, microcrystalline cellulose,micromicrocrystalline cellulose, powdered glycyrrhiza, sodium hydrogencarbonate, calcium phosphate, calcium sulfate, calcium carbonate,precipitated calcium carbonate, calcium silicate and the like, and cornstarch and microcrystalline cellulose are preferable.

Examples of the disintegrant include amino acid, starch, corn starch,carmellose, carmellose sodium, carmellose calcium, croscarmellosesodium, crospovidone, low-substituted hydroxypropylcellulose,hydroxypropyl starch, sodium carboxymethyl starch and the like, andcrospovidone and carmellose are preferable.

In the rapidly disintegrating preparation of the present invention, theaverage particle size of the “granules comprising a medicament coatedwith a coating layer containing sugar or sugar alcohol” is generally 50μm-500 μm, preferably 50 μm-355 μm, more preferably 50 μm-150

In the present specification, the average particle size is a valuemeasured by a laser diffraction particle size analyzer, SYMPATEC:HELOS&RODOS and the like.

In the rapidly disintegrating preparation of the present invention,examples of the disintegrant contained as an extragranule componentinclude amino acid, starch, corn starch, carmellose, carmellose sodium,carmellose calcium, croscarmellose sodium, crospovidone, low-substitutedhydroxypropylcellulose, hydroxypropyl starch, sodium carboxymethylstarch and the like, and crospovidone and carmellose are preferable.

The content of the disintegrant is generally 0.5-15 wt %, preferably1-10 wt %, more preferably 2-5 wt %, relative to the total weight of thepreparation.

In the rapidly disintegrating preparation of the present invention,examples of the lubricant optionally contained as an extragranulecomponent include magnesium stearate, stearic acid, calcium stearate,talc (purified talc), sucrose esters of fatty acid, sodium stearylfumarate and the like, and sodium stearyl fumarate is preferable.

The content of the lubricant is generally 0.5-2 wt %, preferably 0.5-1.5wt %, more preferably 0.5-1 wt %, relative to the total weight of thepreparation.

The rapidly disintegrating preparation of the present invention mayfurther contain an additive as an extragranule component wherenecessary.

Examples of the additive include masking agent, solubilizer and thelike, explained above, which may be used in combination where necessary.

The rapidly disintegrating preparation of the present invention is notonly useful as a so-called “orally disintegratable preparation” aimingat oral administration of a medicament, but also preferable as apreparation for oral-mucosal absorption (particularly, sublingualpreparation, buccal preparation).

The rapidly disintegrating preparation for oral-mucosal absorption ofthe present invention can be expected to show immediate effect byabsorption from the oral mucosa.

While the dosage form of the rapidly disintegrating preparation of thepresent invention is not particularly limited, it is preferably atablet.

When the rapidly disintegrating preparation of the present invention isa tablet, the weight of the preparation is preferably about 20-200 mg.

When the rapidly disintegrating preparation of the present invention isa tablet, the absolute hardness is generally not less than 1.0 N/mm²,preferably not less than 1.5 N/mm², more preferably not less than 2.0N/mm². When the rapidly disintegrating preparation of the presentinvention is a tablet, the absolute hardness is generally not more than5.0 N/mm².

When the rapidly disintegrating preparation of the present invention isa tablet, the disintegration time is generally not more than 30 sec,preferably not more than 15 sec, more preferably not more than 10 sec.When the rapidly disintegrating preparation of the present invention isa tablet, the disintegration time is generally not less than 1 sec.

In the rapidly disintegrating preparation of the present invention, thedisintegration property can be improved by including, in granules, acomponent that prevents disintegration, as described above. In addition,it can achieve high disintegration property by ensuring the invasionroute of water into the preparation by coating the component thatprevents disintegration with sugar or sugar alcohol. Therefore, evenwhen the rapidly disintegrating preparation of the present invention ismolded to have the above-mentioned high absolute hardness, it shows gooddisintegration property. Thus, the rapidly disintegrating preparation ofthe present invention can achieve both the good disintegration propertyand the good preparation hardness.

The rapidly disintegrating preparation of the present inventionpreferably shows a disintegration time of not more than 30 sec, andabsolute hardness of not less than 1.0 N/mm².

The rapidly disintegrating preparation of the present invention can beproduced by a method conventionally used in the pharmaceutical-technicalfield. For example, the preparation can be produced by the followingproduction method of the rapidly disintegrating preparation of thepresent invention.

The production method of the rapidly disintegrating preparation of thepresent invention includes

step (1): producing granules comprising a medicament,

step (2): forming a coating layer containing sugar or sugar alcohol onthe obtained granules, and

step (3): mixing the coated granules with a disintegrant and molding themixture.

In steps (1)-(3), an additive may be further added as necessary. As thekind and amount of the “medicament”, “sugar”, “sugar alcohol”,“disintegrant” and “additive” to be used in steps (1)-(3), thoseexemplified for the above-mentioned rapidly disintegrating preparationcan be mentioned. As the particle size of the coated granules obtainedin step (2), the range exemplified as the particle size of the “granulescomprising a medicament coated with a coating layer containing sugar orsugar alcohol” of the above-mentioned rapidly disintegrating preparationcan be mentioned.

The production of the granule in step (1) and formation of the coatinglayer in step (2) can also be carried out simultaneously.

For example, the preparation can be specifically produced as follows.

Sugar or sugar alcohol (e.g., D-mannitol etc.) is dissolved in asuitable solvent (e.g., water etc.) to give a coating solution.

A medicament (e.g., compound A etc.) and any additive (e.g., excipientsuch as D-mannitol, microcrystalline cellulose and the like, binder suchas partly pregelatinized starch and the like etc.) are mixed to give amixture. The obtained mixture is granulated while spraying the coatingsolution thereon, and dried to give a granulated powder (coatedgranules). The obtained granulated powder (coated granules) may besieved as necessary.

The obtained coated granules, a disintegrant (e.g., crospovidone etc.)and any additive (e.g., lubricant such as sodium stearyl fumarate etc.,and the like) are mixed to give a mixed powder. The obtained mixedpowder is compression-molded to give a tablet.

Here, the mixing (including granulation, drying, sieving and the like)is carried out by using a preparation machine, for example, V-typemixer, tumbler mixer (TM-30, TM-15S; SHOWA KAGAKU KIKAI CO., LTD.:TM20-0-0; Suehiro Kakoki Co., Ltd.), high speed mixer granulator(FM-VG-10; POWREX CORPORATION), universal kneader (HATA IRON WORKS CO.,LTD.), fluid bed dryer granulator (LAB-1, FD-3S, FD-3SN, FD-5S; POWREXCORPORATION), box type vacuum dryer (Kusuki Kikai Seisakusho), powermill grinding machine (P-3, SHOWA KAGAKU KIKAI CO., LTD.),centrifugation rolling granulator (CF-mini, CF-260, CF-360; FreundCorporation), dry type granulator, spray-drying granulator, rollinggranulator (MP-10; POWREX CORPORATION) and the like.

Coating is carried out by using, for example, a preparation machine, forexample, centrifugation rolling granulator (CF-mini, CF-260, CF-360;Freund Corporation), rolling granulator (MP-10; POWREX CORPORATION),general fluidized bed coater, wurster-type coater and the like.

Compression molding is carried out by using, for example, single punchtableting machine (Kikusui Seisakusho Ltd.), rotary tableting machine(AQUARIUS 36K, AQUARIUS 2L; Kikusui Seisakusho Ltd.), AUTOGRAPH(AG-5000B, SHIMADZU Corporation) and the like, and by punching generallyat a pressure of 1-30 kN.

Formulation: A Preparation for Oral-Mucosal Absorption of Compound A

The rapidly disintegrating preparation for oral-mucosal absorption ofthe present invention is particularly effective when a medicament (e.g.,compound A etc.) susceptible to a first pass metabolism effect whenadministered orally is used. The rapidly disintegrating preparation fororal-mucosal absorption of the present invention can improvebioavailability by increasing the blood concentration of suchmedicament. In addition, the rapidly disintegrating preparation fororal-mucosal absorption of the present invention can suppressinconsistent absorption of such medicaments, and further, inconsistenteffectiveness as medicaments. Moreover, the rapidly disintegratingpreparation for oral-mucosal absorption of the present invention canafford a low dose medicament with the potential for fewer side effectswhen it is used for the treatment of a bipolar disorder, such asresidual daytime sleepiness and/or fatigue, and a compact preparationbased on the improved medicament bioavailability.

When compound A is particularly used as a medicament, the rapidlydisintegrating preparation for oral-mucosal absorption of the presentinvention shows an effect in that the ratio of the medicament in anunchanged form to a metabolite of the medicament after transfer intoblood is higher than that by oral administration. In addition, therapidly disintegrating preparation for oral-mucosal absorption of thepresent invention shows not less than about 10-fold improvedbioavailability of compound A, as compared to that by oraladministration.

i. Preparation (A)

That is, the present invention also relates to a preparation fororal-mucosal absorption containing compound A as a medicament; whichshows a higher ratio of the medicament in an unchanged form and ametabolite of the medicament, particularly M-II, after transfer intoblood than that by oral administration (preparations [9] to [11], [17]and [18]) (hereinafter sometimes to be abbreviated as preparation (A) ofthe present invention).

When the dosage form of preparation (A) is a tablet, the disintegrationtime is preferably not more than 30 sec. When the dosage form inpreparation (A) is a tablet, more preferably, the disintegration time isnot more than 30 sec, and the absolute hardness is not less than 1.0N/mm².

The aforementioned preparations [5] to [7] are also encompassed in the“preparation (A)”.

ii. Preparation (B) and Bioavailability

The present invention also relates to a preparation for oral-mucosalabsorption, which contains compound A, and shows not less than about10-fold improved bioavailability of compound A, as compared to that byoral administration (preparations [12] to [18]) (hereinafter sometimesto be abbreviated as preparation (B) of the present invention). Here,“about” means 5% error range. The bioavailability is generally improvedwithin the range of not more than about 30-fold, more specifically notmore than about 25-fold. In other words, the bioavailability is improvedwithin the range from not less than about 10-fold to not more than about30-fold, more specifically, within the range from not less than about10-fold to not more than 25-fold.

When the dosage form of preparation (B) is a tablet, preferably, thedisintegration time is not more than 30 sec. When the dosage form inpreparation (B) is a tablet, more preferably, the disintegration time isnot more than 30 sec, and the absolute hardness is not less than 1.0N/mm².

The aforementioned preparations [5] to [7] are also encompassed in the“preparation (B)”.

Here, whether or not “bioavailability of compound A is improved not lessthan about 10-fold as compared to oral administration” is evaluated asfollows.

Each preparation is administered intravenously, orally ororal-mucosally, the plasma concentration after lapse of each time periodis measured, and the area under the plasma concentration time curve(AUC) is calculated according to the method known in this art. There aretwo kinds of AUC values. One is AUC(0-tlqc), and the other isAUC(0-inf). AUC(0-tlqc) is area under the serum concentration-time curvefrom time 0 to time of the last quantifiable concentration (tlqc),calculated using the linear trapezoidal rule. AUC(0-inf) is area underthe serum concentration-time curve from time 0 to infinity, calculatedas AUC(0-inf)=AUC(0-tlqc)+lqc/λz, where tlqc is the time of lastquantifiable concentration, lqc is the last quantifiable concentration,and λz is terminal elimination rate constant, calculated as the negativeof the slope of the log-linear regression of the natural logarithmconcentration-time curve during the terminal phase. Both AUC values canbe used for evaluation of improvement of bioavailability, but inprinciple, the evaluation thereof is made based on AUC(0-inf) value.

(a) Method A for Calculating Bioavailability Ratio

Bioavailability (BA) is calculated according to the following formula(absolute bioavailability).BA (%)=((oral or oral-mucosal administration AUC/dose in oral ororal-mucosal administration)/(intravenous administration AUC/dose inintravenous administration))×100.

The ratio of the calculated BA by oral-mucosal administration relativeto the calculated BA by oral administration (that is, BA by oral-mucosaladministration/BA by oral administration) is calculated. This ratio isreferred to as “BA ratio” (Method A).

In this case, when the “ratio of the BA by oral-mucosal administrationrelative to the BA by oral administration” (absolute BA ratio) is notless than 10, the preparation is evaluated to show “not less than about10-fold improved bioavailability of compound A as compared to that byoral administration”.

As for the test method, the examples of specific preparations to besubjected to a test, the below-mentioned Experimental Example 3 can bereferred to. However, when a substantially similar evaluation ispossible, the method is not limited to that of Experimental Example 3.

(b) Method B for Calculating Bioavailability Ratio

As for another evaluation method of bioavailability ratio, namely,“ratio of the BA by oral-mucosal administration relative to the BA byoral administration” here, one can calculate it according to thefollowing formula (Method B; relative BA ratio).Relative BA ratio=A/B×100(wherein “A” means oral mucosal administration AUC/dose of compound A inthe oral mucosal preparation administered to a human subject; and “B”means oral administration AUC/dose of compound A in the oral preparationadministered to a human subject)

As for the test method, the examples of specific preparations to besubjected to a test, the below-mentioned Experimental Example 4 can bereferred to. However, when a substantially similar evaluation ispossible, the method is not limited to that of Experimental Example 4.The example demonstrates greater bioavailability of oral-mucosaladministration compared to oral administration.

In this case, when the “ratio of the BA by oral-mucosal administrationrelative to the BA by oral administration” (relative BA ratio) is notless than 10, the preparation is evaluated to show “not less than about10-fold improved bioavailability of compound A as compared to that byoral administration”.

iii. Preparation C and Ratio of Medicament in Unchanged Form toMetabolite of Medicament

The present invention also relates to a preparation for oral-mucosalabsorption, which contains compound A and shows a higher ratio of amedicament in an unchanged form and a metabolite of the medicament aftertransfer into blood than that by oral administration (preparations [9]to [11]) (hereinafter sometimes to be abbreviated as preparation (C) ofthe present invention).

The “greater than the ratio” specifically means not less than about5-fold, preferably not less than about 10-fold. It is generally not morethan about 30-fold, more specifically not more than about 20-fold. Here,“about” means 5% error range.

When the dosage form of preparation (C) is a tablet, preferably, thedisintegration time is not more than 30 sec. When the dosage form ofpreparation (C) is a tablet, more preferably, disintegration time is notmore than 30 sec, and the absolute hardness is not less than 1.0 N/mm².

The aforementioned preparations [5] to [7] are also encompassed in the“preparation (C)”.

Here, whether or not the “ratio of the medicament in an unchanged formand a metabolite of the medicament after transfer into blood is higherthan that by oral administration” is evaluated as follows.

Each preparation is administered orally or oral-mucosally, the plasmaconcentration of both the unchanged form and metabolite after lapse ofeach time period is measured, and the area under the plasmaconcentration time curve (AUC) of the both is calculated according tothe method known in this art. There are two kinds of AUC values. One isAUC(0-tlqc), and the other is AUC(0-inf). AUC(0-tlqc) is area under theserum concentration-time curve from time 0 to time of the lastquantifiable concentration (tlqc), calculated using the lineartrapezoidal rule. AUC(0-inf) is area under the serum concentration-timecurve from time 0 to infinity, calculated asAUC(0-inf)=AUC(0-tlqc)+lqc/λz, where tlqc is the time of lastquantifiable concentration, lqc is the last quantifiable concentration,and λz is terminal elimination rate constant, calculated as the negativeof the slope of the log-linear regression of the natural logarithmconcentration-time curve during the terminal phase.

Both AUC values can be used for evaluation of improvement ofbioavailability, but in principle, the evaluation thereof is made basedon AUC(0-inf) value.

The ratio of the unchanged form and metabolite, (i.e., AUC of unchangedform/AUC of metabolite) in each preparation is calculated.

In this case, when the ratio by oral-mucosal administration is higherthan that by oral administration, it is evaluated “the ratio of amedicament in an unchanged form and a metabolite of the medicament aftertransfer into blood is higher than that by oral administration”.

As for the test method, the examples of specific preparations to besubjected to a test, the below-mentioned Experimental Example 4 isreferenced. However, when a substantially similar evaluation ispossible, the method is not limited to that of Experimental Example 4. Aperson skilled in the art would not have expected the level ofmetabolite, especially, the specific metabolite M-II out of manyexisting metabolites of compound A, by oral-mucosal administration to beas low as demonstrated in this experiment.

While the dosage forms of preparation (A), preparation (B) andpreparation (C) are not particularly limited as long as they can beadministered from the oral mucosa. For example, tablet (e.g., sublingualtablet, buccal tablet), film, troche, solution, suspension, freeze-driedpreparation, chewing gum, spray and the like can be mentioned. Amongthese, tablet is preferable.

As the kind and amount of “compound A”, “masking agent”, “sugar”, “sugaralcohol” and “disintegrant” to be used for preparation (A), preparation(B) or preparation (C), those exemplified for the above-mentionedrapidly disintegrating preparation can be mentioned.

In the present specification, the absolute hardness is hardness per unitarea, and is defined according to the following formula.absolute hardness (N/mm²)=hardness (N)/(thickness (mm)×diameter (mm))

In the present invention, the tablet hardness can be measured by atablet hardness tester (TH-303MP, Toyama Sangyo CO., LTD.).

In the present specification, the disintegration time is a valuemeasured by a disintegration tester (ODT-101, Toyama Sangyo CO., LTD.)for orally rapidly disintegrating tablet.

Formulation: A Preparation for Oral-Mucosal Absorption of Compound A (2)

iv. Preparation D

The present invention also relates to a preparation for oral-mucosalabsorption (preparations [37] to [59]) (hereinafter sometimes to beabbreviated as preparation (D) of the present invention).

As for preparation (D), in principle, definitions of the termsspecifying each preparation [37] to [59] and concrete examples thereofcan be referred to those exemplified for preparations (A) to (C) above.

Concerning preparations [37] to [39], “the AUC ratio of(S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamidein an unchanged form to a metabolite of(S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide(M-II)” means the value calculated by the formula:“AUC of(S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamidein unchanged form/AUC of a metabolite of(S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide(M-II)”.

Here, the term “AUC” and the calculation method thereof can be referredto those exemplified for the preparations (A) to (C) above.

The AUC ratio is not less than about 5-fold than that by oraladministration, preferably, not less than about 10-fold than that byoral administration. In general, the AUC ratio is not more than about30-fold than that by oral administration, more specifically, not morethan about 25-fold than that by oral administration. Here, “about” means5% error range.

As for the test method, the examples of specific preparations to besubjected to a test, the below-mentioned Experimental Example 4 can bereferred to. However, when a substantially similar evaluation ispossible, the method is not limited to that of Experimental Example 4.

Concerning preparations [40] and [41], the AUC ratio of a metabolite of(S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide(M-II) to(S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-5-yl)ethyl]propionamidein an unchanged form means the value calculated by the formula:“AUC of a metabolite of(S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide(M-II)/AUC of(S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamidein unchanged form”.

Here, the term “AUC” and the calculation method thereof can be referredto those exemplified for the preparations (A) to (C) above.

As for the test method, the examples of specific preparations to besubjected to a test, the below-mentioned Experimental Example 4 can bereferred to. However, when a substantially similar evaluation ispossible, the method is not limited to that of Experimental Example 4.

The AUC ratio is not more than about 25, preferably, not more than about10, and more preferably, not more than about 5. In general, the AUCratio is not less than about 1. Here, “about” means 5% error range.

Concerning preparation [42], “the bioavailability of(S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide”can be calculated according to the evaluation method (Method B) asexplained for preparation (B) before.

As for the test method, the examples of specific preparations to besubjected to a test, the below-mentioned Experimental Example 4 can bereferred to. However, when a substantially similar evaluation ispossible, the method is not limited to that of Experimental Example 4.

The bioavailability is not less than about 10-fold improved, as comparedto that by oral administration. Here, “about” means 5% error range. Ingeneral, the bioavailability is improved within the range from not lessthan about 10-fold to not more than about 30-fold, more specifically,within the range from not less than about 10-fold to not more than about25-fold than that by oral administration.

Concerning preparations [43] and [44], in the term of “Tmax value ofplasma level of(S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamideafter administration to a human”, Tmax means time to reach Cmax, whereinCmax means maximum observed serum concentration, after a preparation isadministered to a human.

As for the test method, the examples of specific preparations to besubjected to a test, the below-mentioned Experimental Example 4 can bereferred to. However, when a substantially similar evaluation ispossible, the method is not limited to that of Experimental Example 4.

The average Tmax value is not more than about 0.4 hrs, preferably, notmore than about 0.3 hrs, and more preferably, not more than about 0.25hrs.

Concerning preparations [45] and [46], in the term of “the individualvariability of pharmacokinetic parameters including Cmax and AUC of(S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide(unchanged form) after administration to a human” is expressed in theterm of “coefficient of variation (%)” which is calculated by theformula:standard deviation/mean value for each target pharmacokineticparameter×100

As for the test method, the examples of specific preparations to besubjected to a test, the below-mentioned Experimental Example 4 can bereferred to. However, when a substantially similar evaluation ispossible, the method is not limited to that of Experimental Example 4.

Individual variability is not more than about 45%, more preferably, notmore than about 35%, and most preferably, not more than about 30%. Here,“about” means 5% error range.

Dosage Forms

Preparations (A)-(D) can be produced, for example, according to theproduction method explained for “the rapidly disintegrating preparationof the present invention”. Particularly, when the dosage form ofpreparations (A)-(D) is tablet, such production method is preferable. Itis also possible to apply other techniques for orally disintegratingpreparations.

When the dosage form of preparations (A) (D) is film, the preparationscan be produced according to a conventional method as follows. Forexample, the preparation can be produced by applying or spraying acoating solution (solution or suspension, solvent is, for example,purified water) containing a medicament, a film carrier, other filmcarriers used as necessary and the like to the surface of a supportmedium, and drying same (JP-B-3460538).

When the dosage form of preparations (A)-(D) is freeze-driedpreparation, the preparation can be produced according to a conventionalmethod as follows. For example, the preparation can be produced bymixing a medicament, a polymer, sugars and the like, and dissolving andlyophilizing them (Manufacturing Chemist, February 36 (1990)).

When the dosage form of preparations (A)-(D) is chewing gum, thepreparation can be produced according to a conventional method asfollows. For example, the preparation can be produced by adding amedicament, additive such as sweetener, flavor, colorant, softeningagent, flavoring substance and the like to a gum base containing a resinfor a gum base as a main component, wax, an emulsifier and a filler,uniformly kneading them in a kneader, and processing them into a plateform, a block form and the like (JP-A-2009-136240).

When the dosage form of preparations (A)-(D) is troche, the preparationcan be produced according to a general production method of tablets.

When the dosage form of preparations (A)-(D) is solution or suspension,the preparation can be produced according to a general production methodof liquids.

When the dosage form of preparations (A)-(D) is spray, the preparationcan be produced according to a general production method of spray.

The preparation of the present invention can be safely administered to amammal (e.g., human, mouse, rat, rabbit, dog, cat, bovine, horse, swine,monkey), particularly human.

The dose of the preparation of the present invention varies depending onthe subject of administration, administration route, disease and thelike. For example, when a preparation for oral-mucosal absorptioncontaining compound A as a medicament is administered to an adult, thedose of compound A is about 0.0002-about 0.02 mg/kg body weight,preferably about 0.0002-about 0.01 mg/kg body weight, more preferablyabout 0.0002-about 0.005 mg/kg body weight, most preferably about0.0002-about 0.004 mg/kg body weight, which can be administered in oneto several portions a day, preferably once a day. In other words, asmentioned later, the dose of compound A is 0.05-1.5 mg (preferably,0.05-1.0 mg, more preferably, 0.1-1.0 mg, much more preferably, 0.1-0.8mg and most preferably, 0.1 mg, 0.4 mg and 0.8 mg) a day, which can beadministered once a day.

The solubility of compound A is about 0.2 mg/ml irrespective of pH. Inorder for this compound to be absorbed oral-mucossally, the compoundshould be dissolved in saliva first. When it is taken into considerationthat the amount of saliva in the oral cavity is about 1 ml, thereduction of amount of compound A which the present invention brings inis quite advantageous from practical viewpoint.

According to the preparation of the present invention, as mentionedabove, the dose of compound A can be reduced with keeping its efficacy.Therefore, if necessary, the size of the preparation can be madesmaller. This feature would be also one of the advantages of the presentinvention.

Method of Use of Compound A: Prophylaxis and/or Treatment of a BipolarDisorder

It is known that melatonin secretion decreases to cause disorders in thecircadian rhythm in patients with bipolar disorders. NeuroscienceLetters, 475: 169-173 (2010); Journal of Psychiatric Research, 44:69-74(2010).

When compound A is administered oral-mucosally to a human subject, it issurprisingly observed that the pharmacokinetics (rapid onset and offsetof action) of Compound A is quite similar to that of the endogenousmelatonin, and with the characteristic pharmacokinetic profile, compoundA can regulate the circadian rhythm, which is thought to be disturbed inbipolar patients, better than existing drugs indicated for a bipolardisorder. Thus, when oral-mucosally administered, compound A is expectedto show superior effect on bipolar disease to existing drugs. Inaddition, this circadian rhythm regulating effect can also translateinto better normalizing circadian rhythm and/or sleep/awake cycle inbipolar patients.

As mentioned above, the present invention provides a preparation showingsuperior absorption of compound A from the oral mucosa and improvedbioavailability thereof and characteristic pharmacokinetic profilethereof. For example, when compound A is administered oral-mucosally,the variability of Cmax and AUC between different individuals is lessthan when the compound A is administered orally.

For example, in Table 4, the Cmax of unchanged Compound A and the Cmaxof active metabolite M-II for sublingual administration are 4.74+1.52and 4.18±1.26, respectively, with an unchanged/metabolite ratio of 1.13.In contrast, the corresponding unchanged/metabolite Cmax and ratio fororal administration are 4.76±5.19, 68.1±23.2 and 0.07. The relatedAUC(0-inf) unchanged/metabolite ratios for sublingual and oraladministrations are 0.30 and 0.03, respectively. Accordingly, Table 4demonstrates that a higher ratio of unchanged Compound A to metaboliteis produced with sublingual administration over oral administration.Accordingly, it is believed that sublingual or buccal administrationbypasses first-pass metabolism and, as a result, reduces the variabilitythat exists among patients in the metabolism of Compound A. Hence, amore effective method for the prophylaxis and/or treatment of bipolardisorders, and a more effective drug for the prophylaxis and/ortreatment of bipolar disorders are provided.

To be precise, by oral-mucosal administration of compound A to patientsaffected with bipolar disorders, the bipolar disorders can be preventedand/or treated. Specifically, such prophylaxis and/or treatment can beperformed by appropriately administering compound A in the form of thepreparation of the present invention (preparations (A) to (D)) tohumans. For example, the various kinds of PK profiles mentioned in themethods [59] to [71] can be achieved by administering compound A to ahuman in the forms of preparations [37] to [58].

Here, the administration route of compound A is preferably sublingualadministration or buccal administration, and sublingual administrationis particularly preferable.

The sublingual and buccal administration is advantageous for providing aquick onset of therapy and a quick offset of therapy. This is incontrast to oral administration, in which onset and offset is slower dueto gastro-intestinal transit time. When compared with oraladministration, the sublingual and buccal administrations result in alower ratio of the metabolite M-II to Compound A. By providing a quickoffset, patients affected with biopolar disorders benefit from theeffects of Compound A without experiencing prolonged sleepiness that canbe associated with the presence of the metabolites.

It is believed that the quick onset/quick offset property of sublingualand buccal administrations parallel the effects of endogenous melatonin.In one embodiment, the formulation provides a therapeutic effect byachieving a blood level above a certain therapeutic level for a certainperiod of time. The duration and blood level should correspond to anendogenous melatonin level in a normal individual who does not sufferfrom so bipolar disorder.

While the dose of compound A is as mentioned above, for administrationas a sublingual tablet or a buccal tablet, for example, a tabletcontaining 0.05-1.5 mg (preferably, 0.05-1.0 mg, more preferably,0.1-1.0 mg, much more preferably, 0.1-0.8 mg and most preferably, 0.1mg, 0.4 mg and 0.8 mg) of compound A per tablet is preferablyadministered to patients, preferably, once per day.

As to the target disease, the invention is effective for bipolardisorders including bipolar disorder I, bipolar disorder II (recurrentmajor depressive episodes with hypomanic episodes) (296.89), and bipolardisorder not otherwise specified (296.80). The numbers in brackets afterthe listed diseases above refer to the classification code in Diagnosticand Statistical Manual of Mental Disorders, 4th Edition, published bythe American Psychiatric Association (DSM-IV) and/or the InternationalClassification of Diseases, 10th Edition (ICD-10). However, it should beunderstood that the invention is intended to be used in the treatment ofdiseases related or similar to those described in this classificationcoding system which, of course, may change over time as more isunderstood about these disorders. The invention is particularlyeffective in the treatment of bipolar disorder I. Specifically, it iseffective for the “treatment of depression symptoms (particularly, acutedepression symptoms) associated with bipolar disorder” and “maintenanceof remission phase of bipolar disorder”.

For the “prophylaxis and/or treatment of bipolar disorders byoral-mucosal administration of compound A”, other medicaments for theprophylaxis and/or treatment of bipolar disorders may be used incombination. Such other medicaments for the prophylaxis and/or treatmentof bipolar disorders to be used in combination with “compound A”(hereinafter referred to as “combination medicament”) may include moodstabilizer (e.g. lithium, valproic acid, carbamazepine, lamotrigine,etc) and antipsychotics (e.g. quetiapine, olanzapine, etc), and acombination of one or more medicaments selected from them. In additionthereto, one or more SSRI (selective serotonin reuptake inhibitors)(e.g. fluvoxamine, paroxetine, escitalopram, fluoxetine, citalopram,etc) may also be administered in combination with “compound A” and theaforementioned “combination medicament”.

The administration mode of the “combination medicament” is notparticularly restricted, and it is sufficient that “compound A” and“combination medicament” be combined in administration. Examples of suchadministration mode include the following:

(1) administration of a single preparation obtained by simultaneouslyprocessing “compound A” and “combination medicament”,

(2) simultaneous administration of two kinds of preparations of“compound A” and “combination medicament”, which have been separatelyproduced, by the same administration route,

(3) administration of two kinds of preparations of “compound A” and“combination medicament”, which have been separately produced, by thesame administration route in a staggered manner,

(4) simultaneous administration of two kinds of preparations of“compound A” and “combination medicament”, which have been separatelyproduced, by different administration routes,

(5) administration of two kinds of preparations of “compound A” and“combination medicament”, which have been separately produced, bydifferent administration routes in a staggered manner (e.g.,administration in the order of “compound A” and “combinationmedicament”, or in the reverse order) and the like.

The dosage of the “combination medicament” may be determined accordingto the dose clinically used, and can be appropriately selected dependingon an administration subject, administration route, seriousness of thedisease, combination, and the like.

The “combination medicament” can be administered in the same dosage formas clinically used or in a different dosage form suitable for thiscombination therapy.

EXAMPLES

The present invention is explained in more detail in the following byreferring to Examples, which are not to be construed as limitative. Thepreparation additives (e.g., D-mannitol, microcrystalline cellulose, andthe like) used in the following Examples and Comparative Examples werethe Japanese Pharmacopoeia 15th Edition or Japanese PharmaceuticalExcipients 2003 compatible products.

Example 1

(1) D-Mannitol (PEARLITOL 50C, Roquette) (450.0 g) was dissolved inpurified water (2550 g) to give a coating solution. Compound A (150.5g), D-mannitol (3068 g), microcrystalline cellulose (CEOLUS PH-101,Asahi Kasei Corporation) (112.5 g), and partly pregelatinized starch(PCS, Asahi Kasei Corporation) (450.0 g) were uniformly mixed in a fluidbed dryer granulator (FD-5S, POWREX CORPORATION), granulated whilespraying the coating solution (3000 g), and dried to give a granulatedpowder. A part of the obtained granulated powder was ground in a powermill grinding machine (P-3, SHOWA KAGAKU KIKAI CO., LTD.) using a 1.5mmφ punching screen to give a sieved powder.(2) To the obtained sieved powder (1692 g) were added crospovidone(Kollidon CL-F, BASF) (90 g) and sodium stearyl fumarate (PRUV, JRSPHARMA) (18 g), and the mixture was mixed in a tumbler mixer (TM-30,SHOWA KAGAKU KIKAI CO., LTD.) to give a mixed powder.(3) The mixed powder was tableted by a rotary tableting machine (AQUA08242L2J1, Kikusui Seisakusho Ltd.) using a 4 mmφ punch (tabletingpressure: 4 kN, weight per tablet: 30 mg) to give a tablet.

Composition of preparation (30 mg) compound A 1.0 mg D-mannitol (ingranules) 20.45 mg  D-mannitol (in coating layer) 3.0 mgmicrocrystalline cellulose 0.75 mg  partly pregelatinized starch 3.0 mgcrospovidone 1.5 mg sodium stearyl fumarate 0.3 mg total  30 mg

Comparative Example 1

Polyethylene glycol 400 (PEG400) (Wako Pure Chemical Industries, Ltd.)(15 g) was dissolved in purified water (35 g) to give PEG400 solution.Compound A (12.5 mg) was added to PEG400 solution (50 ml), and themixture was stirred and insonated, and filtered using a hydrophilicfilter (0.45 μm). The obtained compound A solution was divided intosmall portions (1 ml each).

Composition of preparation (1 ml) compound A  0.25 mg PEG400 300.0 mgpurified water 700.0 mg total 1000.25 mg 

Comparative Example 2

(1) Hydroxypropylcellulose (HPC-L, NIPPON SODA CO., LTD.) (40 g) wasdissolved in purified water (627 g) to give a binding solution. CompoundA (2.5 g), lactose (DMV INTERNATIONAL) (1053.5 g), and corn starch(Japan Corn Starch Co., Ltd.) (160 g) were uniformly mixed in a fluidbed dryer granulator (MP-01, POWREX CORPORATION), granulated whilespraying the binding solution (667 g), and dried to give a granulatedpowder. The obtained granules were sieved through a 16 mesh (aperture1.0 mm) sieve to give a sieved powder.(2) Corn starch (17 g) and magnesium stearate (5 g) were added to theobtained sieved powder (628 g) and mixed in a bag to give a mixedpowder.(3) The mixed powder was tableted by a rotary tableting machine (compacttableting machine, Kikusui Seisakusho Ltd.) by using a 4 mmφ punch(tableting pressure: 7 kN, weight per tablet: 130 mg) to give a tablet(core tablet).(4) Hydroxypropylmethylcellulose (TC-5R) (22.44 g) and Copovidone (4.5g) were dissolved in purified water (198 g) and dispersed therein togive dispersion I. Titanium oxide (25 g) and yellow ferric oxide (0.5 g)were dispersed in purified water (450 g) to give dispersion II.Dispersion II was added to dispersion I, and the mixture was stirred togive a coating solution. The coating solution was sprayed on the coretablet obtained in (3) until the weight of the core tablet increased by5 mg per tablet by using a coater (High Coater HC-LAB0, FreundCorporation) to give a film-coated tablet having the followingcomposition.

Composition of preparation (135 mg) compound A 0.25 mg lactose 105.35mg  corn starch 19.4 mg hydroxypropylcellulose  4.0 mg magnesiumstearate  1.0 mg hydroxypropylmethylcellulose 3.74 mg Copovidone 0.75 mgtitanium oxide  0.5 mg yellow ferric oxide 0.01 mg total  135 mg

Example 2

(1) D-Mannitol (PEARITOL 50C, Roquette) (120 g) was dissolved inpurified water (680 g) to give a coating solution. Compound A (10 g),D-mannitol (848 g), microcrystalline cellulose (CEOLUS PH-101, AsahiKasei Corporation) (30 g), and partly pregelatinized starch (PCS, AsahiKasei Corporation) (120 g) were uniformly mixed in a fluid bed dryergranulator (MP-01, POWREX CORPORATION), granulated while spraying acoating solution (800 g), and dried to give a granulated powder. Theobtained granules were sieved through a 16 mesh (aperture 1.0 mm) sieveto give a sieved powder.(2) The obtained sieved powder (28.2 g), crospovidone (Kollidon CL-F,BASF) (1.5 g) and sodium stearyl fumarate (0.3 g) were mixed in a glassbottle. The obtained mixture was tableted (tableting pressure: 3KN/punch, tablet weight per tablet: 30 mg) by an AUTOGRAPH (AG-5000B,SHIMADZU Corporation) using a 4 mmφ punch to give a core tablet with thefollowing composition.

Composition of preparation (30 mg) compound A 0.25 mg  D-mannitol (ingranules) 21.2 mg  D-mannitol (in coating layer) 3.0 mg microcrystallinecellulose 0.75 mg  partly pregelatinized starch 3.0 mg crospovidone 1.5mg sodium stearyl fumarate 0.3 mg total  30 mg

Comparative Example 3

PEG400 (Wako Pure Chemical Industries, Ltd.) (60 g) was dissolved inpurified water (110 g) to give PEG400 solution. Compound A (100.0 mg)was added to the PEG400 solution (100 ml), and the mixture was stirredand insonated, and filtered using a hydrophilic filter (0.45 μm). Theobtained compound A solution was divided into small portions (1 mleach).

Composition of preparation (1 ml) compound A  1.0 mg PEG400 352.9 mgpurified water 647.1 mg total  1001 mg

Comparative Example 4

(1) Hydroxypropylcellulose (HPC-L, NIPPON SODA CO., LTD.) (660 g) wasdissolved in purified water (10230 g) to give a binding solution.Compound A (165.3 g), lactose (DMV INTERNATIONAL) (17260 g), and cornstarch (Japan Corn Starch Co., Ltd.) (2640 g) were uniformly mixed in afluid bed dryer granulator (FD-S2, POWREX CORPORATION), granulated whilespraying a binding solution (10890 g), and dried to give a granulatedpowder. This granulation step was performed twice. A part of theobtained granulated powder was ground by a power mill grinding machine(5-3, SHOWA KAGAKU KIKAI CO., LTD.) using a 1.5 mmφ punching screen togive a sieved powder.(2) Corn starch (1013 g) and magnesium stearate (298 g) were added tothe obtained sieved powder (37430 g), and the mixture was mixed in atumbler mixer (TM20-0-0, Suehiro Kakoki Co., Ltd.) to give a mixedpowder.(3) The mixed powder was tableted by a rotary tableting machine(AQUARIUS 36K, Kikusui Seisakusho Ltd.) by using a 7 mmφ punch(tableting pressure: 7 kN, weight per tablet: 130 mg) to give a tablet(core tablet).(4) Hydroxypropylmethylcellulose (TC-5R, Shin-Etsu Chemical Co., Ltd.)(1548 g) and Copovidone (310.5 g) were dissolved in purified water(16150 g) and dispersed therein to give dispersion I. Titanium oxide(207 g) and yellow ferric oxide (4.14 g) were dispersed in purifiedwater (1822 g) to give dispersion II. Dispersion II was added todispersion I, and the mixture was stirred to give a coating solution.Using a coater (High Coater HCF-100N, Freund Corporation), the coatingsolution was sprayed on the core tablet obtained in (3) until the weightof the core tablet increased by 5 mg per tablet to give a film-coatedtablet having the following composition.

Composition of preparation (135 mg) compound A  1.0 mg lactose 104.6 mg corn starch 19.4 mg hydroxypropylcellulose  4.0 mg magnesium stearate 1.0 mg hydroxypropylmethylcellulose 3.74 mg Copovidone 0.75 mg titaniumoxide  0.5 mg yellow ferric oxide 0.01 mg total  135 mg

Example 3

(1) D-mannitol (PEARLITOL 50C, Roquette) (120 g) was dissolved inpurified water (680 g) to give a coating solution. Compound A (40 g),D-mannitol (818 g), microcrystalline cellulose (CEOLUS PH-101, AsahiKasei Corporation) (30 g), and partly pregelatinized starch (PCS, AsahiKasei Corporation) (120 g) were uniformly mixed in a fluid bed dryergranulator (MP-01, POWREX CORPORATION), granulated while spraying thecoating solution (800 g), and dried to give a granulated powder. Theobtained granules were sieved through a 16 mesh (aperture 1.0 mm) sieveto give a sieved powder.(2) The obtained sieved powder (28.2 g), crospovidone (Kollidon CL-F,BASF) (1.5 g) and sodium stearyl fumarate (0.3 g) were mixed in a glassbottle. The obtained mixture was tableted (tableting pressure: 3KN/punch, tablet weight per tablet: 30 mg) by an AUTOGRAPH (AG-5000B,SHIMADZU Corporation) by using a 4 mmφ punch to give a core tablet withthe following composition.

Composition of preparation (30 mg) compound A 1.0 mg D-mannitol (ingranules) 20.45 mg  D-mannitol (in coating layer) 3.0 mgmicrocrystalline cellulose 0.75 mg  partly pregelatinized starch 3.0 mgcrospovidone 1.5 mg sodium stearyl fumarate 0.3 mg total  30 mg

Example 4

Compound A (5 g) and CMEC (20 g) were dissolved in acetone:ethanol=3:2mixed solution (500 ml), and spray-dried by a spray dryer (Pulvis MiniSpray, YAMATO SCIENTIFIC CO., LTD.). The obtained solid dispersionpowder was dried in vacuo at 40° C. for 16 hr. To the solid dispersionpowder (0.5 g) was added D-mannitol (PEARLITOL 100SD, Roquette) (11.5 g)and mixed in a bottle. The obtained mixed powder was divided into smallportions (120 mg each).

Composition of preparation (120 mg) compound A 1.0 mg CMEC 4.0 mgD-mannitol 115.0 mg  total 120 mg 

Example 5

Hydroxypropyl-β-cyclodextrin (hereinafter sometimes referred to asHP-β-CyD) (KLEPTOSE HPB, Roquette) (75 g) was dissolved in purifiedwater (422.5 g). Compound A (2.5 g) was dissolved in the obtainedHP-β-CyD aqueous solution to give a coating solution. D-Mannitol(PEARLITOL 500, Roquette) (200 g) and microcrystalline cellulose (CEOLUSPH-101, Asahi Kasei Corporation) (7.5 g) were uniformly mixed in a fluidbed dryer granulator (MP-01, POWREX CORPORATION), granulated whilespraying the coating solution (500 g), and dried to give a granulatedpowder. The obtained granules were sieved through a 16 mesh (aperture1.0 mm) sieve to give a sieved powder. The obtained sieved powder wasdivided into small portions (114 mg each).

Composition of preparation (114 mg) compound A  1.0 mg HP-β-CyD 30.0 mgD-mannitol 80.0 mg microcrystalline cellulose  3.0 mg total  114 mg

Example 6

(1) D-Mannitol (PEARLITOL 50C, Roquette) (450 g) was dissolved inpurified water (2550 g) to give a coating solution. Compound A (37.6 g),D-mannitol (3180 g), microcrystalline cellulose (CEOLUS PH-101, AsahiKasei Corporation) (112.5 g), and partly pregelatinized starch (PCS,Asahi Kasei Corporation) (450 g) were uniformly mixed in a fluid beddryer granulator (FD-5S, POWREX CORPORATION), granulated while sprayingthe coating solution (3000 g), and dried to give a granulated powder. Apart of the obtained granulated powder was ground by a power millgrinding machine (P-3, SHOWA KAGAKU KIKAI CO., LTD.) using a 1.5 mmφpunching screen to give a sieved powder.(2) Crospovidone (Kollidon CL-F, BASF) (90 g) and sodium stearylfumarate (18 g) were added to the obtained sieved powder (1692 g), andthe mixture was mixed in a tumbler mixer (TM-15S, SHOWA KAGAKU KIKAICO., LTD.) to give a mixed powder.(3) The mixed powder was tableted by a rotary tableting machine(AQUARIUS 2L, Kikusui Seisakusho Ltd.) by using a 4 mmφ punch (tabletingpressure: 4 kN, weight per tablet: 30 mg) to give a core tablet with thefollowing composition.

Composition of preparation (30 mg) compound A 0.25 mg  D-mannitol (ingranules) 21.2 mg  D-mannitol (in coating layer) 3.0 mg microcrystallinecellulose 0.75 mg  partly pregelatinized starch 3.0 mg crospovidone 1.5mg sodium stearyl fumarate 0.3 mg total  30 mg

Example 7

(1) D-mannitol (PEARLITOL 50C, Roquette) (450 g) was dissolved inpurified water (2550 g) to give a coating solution. Compound A (150.5g), D-mannitol (3068 g), microcrystalline cellulose (CEOLUS PH-101,Asahi Kasei Corporation) (112.5 g), and partly pregelatinized starch(PCS, Asahi Kasei Corporation) (450 g) were uniformly mixed in a fluidbed dryer granulator (FD-5S, POWREX CORPORATION), granulated whilespraying the coating solution (3000 g), and dried to give a granulatedpowder. A part of the obtained granulated powder was ground by a powermill grinding machine (P-3, SHOWA KAGAKU KIKAI CO., LTD.) using a 1.5mmφ punching screen to give a sieved powder.(2) Crospovidone (Kollidon CL-F, BASF) (90 g) and sodium stearylfumarate (18 g) were added to the obtained sieved powder (1692 g), andthe mixture was mixed in a tumbler mixer (TM-15S, SHOWA KAGAKU KIKAICO., LTD.) to give a mixed powder.(3) The mixed powder was tableted by a rotary tableting machine(AQUARIUS 2L, Kikusui Seisakusho Ltd.) by using a 4 mmφ punch (tabletingpressure: 4 kN, weight per tablet: 30 mg) to give a core tablet with thefollowing composition.

Composition of preparation (30 mg) compound A 1.0 mg D-mannitol (ingranules) 20.45 mg  D-mannitol (in coating layer) 3.0 mgmicrocrystalline cellulose 0.75 mg  partly pregelatinized starch 3.0 mgcrospovidone 1.5 mg sodium stearyl fumarate 0.3 mg total  30 mg

Comparative Example 5

(1) Hydroxypropylcellulose (HPC-L, NIPPON SODA CO., LTD.) (660 g) wasdissolved in purified water (10230 g) to give a binding solution.Compound A (1320 g), lactose (DMV INTERNATIONAL) (16104 g), and cornstarch (Japan Corn Starch Co., Ltd.) (2640 g) were uniformly mixed in afluid bed dryer granulator (FD-S2, POWREX CORPORATION), granulated whilespraying the binding solution (10890 g), and dried to give a granulatedpowder. This granulation step was performed twice. A part of theobtained granulated powder was ground by a power mill grinding machine(P-3, SHOWA KAGAKU KIKAI CO., LTD.) using a 1.5 mmφ punching screen togive a sieved powder.(2) Corn starch (1013 g) and magnesium stearate (298 g) were added tothe obtained sieved powder (37430 g), and the mixture was mixed in atumbler mixer (TM20-0-0, Suehiro Kakoki Co., Ltd.) to give a mixedpowder.(3) The mixed powder was tableted by a rotary tableting machine(AQUARIUS 36K, Kikusui Seisakusho Ltd.) by using a 7 mmφ punch(tableting pressure: 7 kN, weight per tablet: 130 mg) to give a tablet(core tablet).(4) Hydroxypropylmethylcellulose (TC-5R, Shin-Etsu Chemical Co., Ltd.)(1548 g) and Copovidone (310.5 g) were dissolved and dispersed inpurified water (16150 g) to give dispersion I. Titanium oxide (207 g)and yellow ferric oxide (4.14 g) were dispersed in purified water (1822g) to give dispersion II. Dispersion II was added to dispersion I, andthe mixture was stirred to give a coating solution. Using a coater (HighCoater HCF-100N, Freund Corporation), the coating solution was sprayedon the core tablet obtained in (3) until the weight of the core tabletincreased by 5 mg per tablet to give a film-coated tablet having thefollowing composition.

Composition of preparation (135 mg) compound A  8.0 mg lactose 97.6 mgcorn starch 19.4 mg hydroxypropylcellulose  4.0 mg magnesium stearate 1.0 mg hydroxypropylmethylcellulose 3.74 mg Copovidone 0.75 mg titaniumoxide  0.5 mg yellow ferric oxide 0.01 mg total  135 mg

Example 8

(1) D-Mannitol (PEARLITOL 50C, Roquette) (510 g) was dissolved inpurified water (2890 g) to give a coating solution. Compound A (17.05g), O-mannitol (3114 g), microcrystalline cellulose (CEOLUS PH-101,Asahi Kasei Corporation) (127.5 g), and partly pregelatinized starch(PCS, Asahi Kasei Corporation) (510 g) were uniformly mixed in a fluidbed dryer granulator (FD-5S, POWREX CORPORATION), granulated whilespraying the coating solution (3400 g), and dried to give a granulatedpowder. A part of the obtained granulated powder was sieved using around sieve (mesh size 1.0 mmφ) to give sieved powder A.(2) The same step as (1) was performed to give sieved powder B.(3) To the obtained sieved powder A (3146.5 g) and sieved powder B(3146.5 g) were added crospovidone (Kollidon CL-F, BASF) (375.0 g),aspartame (750 g), vanillin (7.5 g) and sodium stearyl fumarate (75 g),and the mixture was mixed in a tumbler mixer (TM-60S, SHOWA KAGAKU KIKAICO., LTD.) to give a mixed powder.(4) The mixed powder was tableted by a rotary tableting machine(AQUARIUS 2L, Kikusui Seisakusho Ltd.) using a 4 mmφ punch (tabletingpressure: 4 kN, weight per tablet: 30 mg) to give a core tablet with thefollowing composition.

Composition of preparation (30 mg) compound A 0.1 mg D-mannitol (ingranules) 18.32 mg  D-mannitol (in coating layer) 3.0 mgmicrocrystalline cellulose 0.75 mg  partly pregelatinized starch 3.0 mgcrospovidone 1.5 mg sodium stearyl fumarate 0.3 mg aspartame 3.0 mgvanillin 0.03 mg  total  30 mg

Example 9

(1) D-Mannitol (PEARLITOL 50C, Roquette) (510 g) was dissolved inpurified water (2890 g) to give a coating solution. Compound A (68.20g), D-mannitol (3063 g), microcrystalline cellulose (CEOLUS PH-101,Asahi Kasei Corporation) (127.5 g), and partly pregelatinized starch(PCS, Asahi Kasei Corporation) (510 g) were uniformly mixed in a fluidbed dryer granulator (FD-5S, POWREX CORPORATION), granulated whilespraying the coating solution (3400 g), and dried to give a granulatedpowder. A part of the obtained granulated powder was sieved by using around sieve (mesh size 1.0 mmφ) to give sieved powder A.(2) The same step as (1) was performed to give sieved powder B.(3) To the obtained sieved powder A (3146.5 g) and sieved powder B(3146.5 g) were added crospovidone (Kollidon CL-F, BASF) (375.0 g),aspartame (750 g), vanillin (7.5 g) and sodium stearyl fumarate (75 g),and the mixture was mixed in a tumbler mixer (TM-60S, SHOWA KAGAKU KIKAICO., LTD.) to give a mixed powder.(4) The mixed powder was tableted by a rotary tableting machine(AQUARIUS 2L, Kikusui Seisakusho Ltd.) using a 4 mmφ punch (tabletingpressure: 4 kN, weight per tablet: 30 mg) to give a core tablet with thefollowing composition.

Composition of preparation (30 mg) compound A 0.4 mg D-mannitol (ingranules) 18.02 mg  D-mannitol (in coating layer) 3.0 mgmicrocrystalline cellulose 0.75 mg  partly pregelatinized starch 3.0 mgcrospovidone 1.5 mg sodium stearyl fumarate 0.3 mg aspartame 3.0 mgvanillin 0.03 mg  total  30 mg

Example 10

(1) D-Mannitol (PEARLITOL 50C, Roquette) (510 g) was dissolved inpurified water (2890 g) to give a coating solution. Compound A (136.4g), D-mannitol (2995 g), microcrystalline cellulose (CEOLUS PH-101,Asahi Kasei Corporation) (127.5 g), and partly pregelatinized starch(PCS, Asahi Kasei Corporation) (510 g) were uniformly mixed in a fluidbed dryer granulator (FD-5S, POWREX CORPORATION), granulated whilespraying the coating solution (3400 g), and dried to give a granulatedpowder. A part of the obtained granulated powder was sieved by using around sieve (mesh size 1.0 mmφ) to give sieved powder A.(2) The same step as (1) was performed to give sieved powder B.(3) To the obtained sieved powder A (3146.5 g) and sieved powder B(3146.5 g) were added crospovidone (Kollidon CL-F, BASF) (375.0 g),aspartame (750 g), vanillin (7.5 g) and sodium stearyl fumarate (75 g),and the mixture was mixed in a tumbler mixer (TM-60S, SHOWA KAGAKU KIKAICO., LTD.) to give a mixed powder.(4) The mixed powder was tableted by a rotary tableting machine(AQUARIUS 2L, Kikusui Seisakusho Ltd.) using a 4 mmφ punch (tabletingpressure: 4 kN, weight per tablet: 30 mg) to give a core tablet with thefollowing composition.

Composition of preparation (30 mg) compound A 0.8 mg D-mannitol (ingranules) 17.62 mg  D-mannitol (in coating layer) 3.0 mgmicrocrystalline cellulose 0.75 mg  partly pregelatinized starch 3.0 mgcrospovidone 1.5 mg sodium stearyl fumarate 0.3 mg aspartame 3.0 mgvanillin 0.03 mg  total  30 mg

Experimental Example 1

The tablet obtained in Example 1 was measured for the tablet hardnessand disintegration time. The tablet hardness was measured by a tablethardness tester (TH-303 MP, Toyama Sangyo CO., LTD.) (n=10). Thedisintegration time was measured by a disintegration tester (ODT-101,Toyama Sangyo CO., LTD.) (n=6). The results are shown in Table 1.

Disintegration Tester Conditions

rotation number: 50 rpm

plummet: 15 mmφ, (10 g)

TABLE 1 hardness 21N absolute hardness 2.73N/mm² disintegration 5.24 sec

Experimental Example 2

The mixed powder obtained in Example 1 was measured for the dissolutionproperty. The mixed powder (15 g) (corresponding to 500 mg of compoundA) was placed in the Japanese Pharmacopoeia 2nd fluid (500 ml), and thedissolution property was evaluated by the Paddle Method, rotation number25 rpm, 37° C. After adding the sample, the eluate was sampled with time(0.25 min, 0.5 min, 0.75 min, 1 min, 5 min, 15 min, 30 min), filtered byusing a hydrophilic filter (0.45 μm), dissolved by 10-fold diluting withthe extract (water/acetonitrile mixed solution (1:1)), and quantified byhigh performance liquid column chromatography (HPLC) under the followingconditions to calculate the solubility. The results are shown in Table2.

HPLC Conditions

detector: ultraviolet ray absorption spectrophotometer

measurement wavelength: 240 nm

column: YMC-Pack ODS-AM AM-307, 5 μm, inner diameter: 4.6 mm

length: 75 mm

column temperature: 25° C.

mobile phase: 0.01 mol/L phosphate buffer/acetonitrile mixed solution(5:3)

flow: 1.2 ml/min

TABLE 2 time (min) compound A concentration (mg/ml) 0 0 0.25 0.103 0.50.218 0.75 0.225 1 0.237 5 0.273 15 0.279 30 0.280

Experimental Example 3

The injections obtained in Comparative Examples 1, 3, oral tabletsobtained in Comparative Examples 2, 4 and preparations for oral-mucosalabsorption obtained in Examples 2-5 were measured for blood kineticsafter intravenous injection, oral, sublingual and buccal administrationsin Macaca fascicularis under fasting conditions. The plasmaconcentration before administration, and 5 min, 10 min, 20 min, 30 min,60 min, 120 min, 240 min and 360 min after administration was measured,and the area under the plasma concentration time curve (AUC) wascalculated according to the trapezoidal rule. In addition,bioavailability (BA) was determined by calculating the ratio of AUC byoral, sublingual or buccal administration to AUC by intravenousinjection. The results are shown in Table 3.

TABLE 3 administration dose (mg) route preparation T_(max) (min) C_(max)(ng/ml) AUC (ng · min/ml) BA (%) 0.25 intravenous Comparative 9.0 ± 6.563.4 ± 14.1 2933.8 ± 578.5  — injection Example 1 oral Comparative 132.0± 130.1 0.4 ± 0.1 54.4 ± 22.6  1.9 Example 2 sublingual Example 2 34.0 ±15.2 12.5 ± 5.9  1218.0 ± 655.8  41.5 buccal Example 6 36.0 ± 18.0 22.7± 12.3 1656.0 ± 726.0  56.4 1 intravenous Comparative 3.2 ± 1.6 509.7 ±248.9 16889.5 ± 2057.2  — injection Example 3 oral Comparative  8.0 ±13.0 0.8 ± 1.2 21.3 ± 35.8  0.1 Example 4 sublingual Example 3 28.0 ±4.5  38.5 ± 12.8 3062.4 ± 1129.9 18.1 Example 4 42.0 ± 16.0 31.4 ± 8.6 3206.9 ± 809.9  19.0 Example 5 48.0 ± 16.0 46.6 ± 13.8 4568.4 ± 1286.327.0 buccal Example 7 36.0 ± 12.0 87.1 ± 21.2 5862.0 ± 1038.0 34.7

Experimental Example 4

Oral preparation and preparation for oral-mucosal absorption weremeasured for blood kinetics of unchanged form and active metabolite M-IIafter oral or sublingual administration to human. The plasmaconcentration before administration, and 5 min, 10 min, 15 min, 20 min,30 min, 45 min, 60 min, 90 min, 120 min, 180 min, 240 min, 360 min, 480min, 600 min, 720 min and 1440 min after administration was measured.

The results are shown in Table 4. To be specific, symbol/term anddefinition thereof in this table are explained in the following. Thestudy was conducted by cross-over method under open-label condition.

AUC(0-tlqc): Area under the serum concentration-time curve from time 0to time of the last quantifiable concentration (tlqc), calculated usingthe linear trapezoidal rule.

AUC(0-inf): Area under the serum concentration-time curve from time 0 toinfinity, calculated as AUC(0-inf)-AUC(0-tlqc)+lqc/λz, where tlqc is thetime of last quantifiable concentration and lqc is the last quantifiableconcentration.

λz: Terminal elimination rate constant, calculated as the negative ofthe slope of the log-linear regression of the natural logarithmconcentration-time curve during the terminal phase.

Cmax: Maximum observed serum concentration.

Tmax: Time to reach Cmax.

Active metabolise M-II:(2S)-2-Hydroxy-N-{2-[(8S)-1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl]ethyl}propanamide

TABLE 4 measurement administration Tmax(a) substance dose (mg) routepreparation (hr) unchanged 8 Oral Comparative 0.75 form (n = 23) Example8 (0.33, 2.00) 0.5 Sublingual Example 6 0.25 (n = 24) (two tablets)(0.15, 0.50) active 8 Oral Comparative 1.00 metabolite (n = 23) Example8 (0.50, 3.00) M-II 0.5 Sublingual Example 6 0.75 (n = 24) (two tablets)(0.25, 1.00) measurement Cmax AUC(0-tlqc) AUC(0-inf) substance dose (mg)(ng/ml) (ng · hr/ml) (ng · hr/ml) unchanged 8  4.76 ± 5.208(b)  6.08 ± 5.57 ± form (c) 109 6.374(b) 5.765(b)(d) (c) 105 (c) 104 0.5  4.74 ±1.508(b)  3.59 ±  3.73 ± (c) 32 1.077(b) 1.124(b)(e) (c) 30 (c) 30active 8 68.10 ± 23.315(b) 208.25 ± 212.45 ± metabolite (c) 34 83.426(b)84.314(b) M-II (c) 40 (c) 40 0.5  4.18 ± 1.247(b)  9.94 ±  12.18 ± (c)30 4.677(b) 4.790(b) (c) 47 (c) 39 (a)Median (min, max) is presented.(b)Mean ± SD is presented. (c) Arithmetic Mean (% CV) is presented. (d)n= 22 (e)n = 23

Example 11

A methylcellulose powder (0.5 g) was dissolved in water (99.5 g) underice-cooling, and compound A (100 mg) was added to the obtained solution(10 ml), stirred and uniformly dispersed therein. The obtainedsuspension was filled in a spray device (spray amount: 100 μL/time) togive an oral spray preparation.

Example 12

Hydroxypropyl-β-cyclodextrin (HP-β-CyD) (40 g) was dissolved in water(60 g), and compound A (100 mg) was added to the obtained solution (10ml), stirred and dissolved therein. The obtained solution was filled ina spray device (spray amount: 100 μL/time) to give an oral spraypreparation.

Example 13

Compound A (100 mg), polyvinylpyrrolidone (1 g) andhydroxypropylcellulose (18 g) were added to ethanol (100 ml) anddissolved by stirring. The obtained solution (1 ml) was spread flat on aplastic sheet and dried to give an orally rapidly dissolving filmpreparation.

Example 14

Compound A (100 mg), D-mannitol (5 g) and hydroxypropylcellulose (100mg) were added to a mixed solution (100 ml) of water and ethanol (4:1)and dissolved by stirring. The obtained solution (1 ml) was dispensed toa pocket of a blister pack with vinyl chloride resin as an inner film,frozen at −30° C., and dried by a vacuum dryer to give an orally rapidlydissolving freeze-dried preparation.

Experimental Example 5 Therapeutic Effectiveness on Maintenance ofRemission Phase in Patients with Bipolar Disorder

1. Test Tablet

Oral 8 mg formulation containing Compound A

2. Test Method

The test tablet was administered to a group of patients suffering frombiopolar disorder and in the remission phase, once daily at bedtime for6 months. A placebo was administered once daily at bedtime to a separatecontrol group of patients in the remission phase of biopolar disorderfor 6 months. This study was performed as a double-blind, randomized,placebo-controlled trial. The time from randomization to relapse over 6months of treatment is determined by the Primary Investigator (PI) ordefined by any of the following criteria: depression [Montgomery-AsbergDepression Rating Scale (MADRS) score≧16]; mania/hypomania [Young ManiaRating Scale (YMRS) total score≧14]; clinical global impressions bipolarversion (CGI-EP); cumulative proportion of participants in each aim(placebo or Compound A) surviving without relapse [MADRS score≧16 andYMRS total score≧14], a medication initiation or change formanic/depressed/mixed symptoms, a hospitalization formanic/depressed/mixed symptoms and suicide risk or imminent risk ofsuicide.

3. Test Result

The test results are presented in Table 5:

TABLE 5 Compound A (Ramelteon) Placebo Number of Participants Analyzed42 41 Cumulative Proportion of Patients in each arm surviving withoutrelapse Baseline 1.00 1.00 Month 1 0.929 0.951 Month 2 0.849 0.588 Month3 0.716 0.448 Month 4 0.661 0.384 Month 5 0.632 0.320 Month 6 0.5660.320

As Table 5 demonstrates, the group of bipolar patients in the remissionphase receiving Compound A had a greater survival rate than patientsreceiving the placebo. This demonstrates that Compound A is effective intreating biopolar patients and keeping them in the remission phase.

Experimental Example 6 Therapeutic Effectiveness on Acute Depression inPatients with Bipolar Disorder

1. Test Tablet

Oral 8 mg formulation containing Compound A

2. Test Method

The test tablet was administered once daily to a group of is patientssuffering from biopolar disorder and in the mania phase for up to 8weeks. A placebo was administered to a separate control group ofpatients in the mania phase of biopolar disorder for up to 8 weeks. Thisstudy was performed as a double-blind, randomized, placebo-controlledtrial. The time from randomization to relapse over 6 months of treatmentis determined by the Primary Investigator (PI) or defined by any of thefollowing criteria: clinical global impressions scale for biopolardisorder (CGI-BP).

3. Test Result

Longitudinal analysis of change in outcome revealed a CGI-BP severityfor depression of −0.1 (−0.16 to −0.05), wherein a value below 0 favorsCompound A (95% Cl; N=9; P value=0.001). This result indicates thatCompound A might have decreased depressive symptoms.

Experimental Example 7 Pharmacokinetic Parameters

1. Test Protocol

A randomized, open-label study to assess the pharmacokinetic parametersof an oral-mucosal tablet containing Compound A and its bioavailabilityrelative to an oral 8 mg tablet containing Compound A was performed.

The test was conducted in two parts: (1) a parallel-group design toevaluate the pharmacokinetic parameters of 3 doses of Compound A (0.25,0.5 and 1 mg) in oral-mucosal tablets and (2) an open-label, randomized2-period crossover design to assess the relative bioavailability(pharmacokinetic profile) of the oral-mucosal 0.5 mg tablet comparedwith the bioavailability of the oral 8 mg tablet.

For part (1), a total of 18 subjects were randomly assigned to 1 of the3 dosing regimens (i.e., 0.25, 0.5 and 1 mg; 6 subjects per dose) andeach subject received a single dose of Compound A at the assigned dose.

For part (2), a total of 24 subjects were randomly assigned to takeeither the oral-mucosal 0.5 mg tablet or the oral 8 mg tablet at asingle dose during each of the two periods.

To evaluate the studies, the pharmacokinetic parameters of Compound Aand M-II were measured, including maximum observed serum concentration(Cmax) and area under the serum concentration-time curve from time 0 tothe last quantifiable concentration (AUC(0-tlqc)).

2. Test Results

The results of the test are provided in the two tables below and inFIGS. 1 and 2.

For part (1), the mean Cmax and AUC(0-tlqc) values of Compound Aincreased with oral-mucosal dose in a dose proportional manner between0.25 and 0.5 mg and in a less than dose proportional manner between 0.5and 1.0 mg. M-II values increased with oral-mucosal dose in an apparentdose proportional manner between 0.25 and 1.0 mg. The intersubjectvariability for both Compound A and M-II ranged from 11% to 66%.

For part (2), regarding Cmax and AUC(0-tlqc), much larger inter-subjectvariability for the oral 8 mg table (% CV ranges from 104% to 109%) thanfor the oral-mucosal tables (% CV ranges from 30% to 32%) was observed.The geometric means for Cmax and AUC(0-tlqc) were considered moreappropriate than arithmetic means for comparison purposes, revealingthat the mean Cmax values of Compound A after oral-mucosaladministration were greater compared to oral administration of the 8 mgtablet. The geometric mean of AUC(0-tlqc) for Compound A were similarbetween the oral-mucosal and oral administrations. Also, the geometricmean Cmax and AUC(0-tlqc) values of M-II were much lower afteroral-mucosal administration when compared with M-II after administrationof the oral tablet. The inter-subject variability values for M-II weresimilar between both the oral-mucosal and oral regimes, ranging from 18%to 47%.

Therefore, the 0.5 mg oral-mucosal dose provided an increase in maximumexposure (as measured by Cmax) and similar total exposure (as measuredby AUC) to Compound A compared to the oral 8 mg tablet. Correspondingly,the oral-mucosal administration provided a small fraction of exposure(<7%) to M-II compared to the approved oral 8 mg tablet.

measurement Dose Cmax AUC(0-tlqc) substance (mg) Statistic (ng/ml) (ng ·hr/ml) unchanged 0.25 N 6 6 form of Mean 3.14 2.60 compound A SD 1.2600.780 % CV 40 30 0.5 N 6 6 Mean 5.85 6.23 SD 2.009 4.026 % CV 34 65 1 N6 6 Mean 9.57 7.87 SD 2.372 2.916 % CV 25 37 active 0.25 N 6 6metabolite Mean 1.85 4.64 M-II SD 0.717 2.887 % CV 39 62 0.5 N 6 6 Mean3.74 10.53 SD 1.093 4.059 % CV 29 39 1 N 6 6 Mean 7.68 20.18 SD 2.8215.538 % CV 37 27

Based on the data above as well as the data presented in Table 4, thepredicted pharmacokinetic parameters for 0.1 mg, 0.4 mg and 0.8 mgsublingual tablets were calculated using the following method.

A 2 compartment model for the unchanged form of compound A and 1compartment model for its metabolite M-II was used to fit PK profilesafter the administration of 0.25 mg, 0.5 mg and 1 mg doses,respectively. The Bayesian parameter estimates were subsequently mappedsuch that individual parameter estimates for 0.25 mg, 0.5 mg, and 1 mgdoses corresponded to the 0.1 mg, 0.4 mg, and 0.8 mg doses,respectively, during simulation. Descriptive statistics were calculatedbased on the individual simulated Cmax and AUC values includinggeometric mean and corresponding 95% and 80% lower and upper geometricmean confidence intervals (CI).

The predicted geometric mean values and the geometric mean confidenceintervals thus obtained are shown in the following.

Geometric Mean (Lower- Upper Geometric 95% CI) Dose (mg) Cmax (ng/mL)AUC(0-tlqc) (ng · hr/mL) Predicted Compound A Exposure 0.1 1.17(0.43-3.13) 1.04 (0.48-2.26) 0.4 3.75 (2.04-6.89) 3.18 (1.52-6.68) 0.87.15 (3.63-14.06) 5.98 (2.48-14.43) Predicted M-II Exposure 0.1 0.69(0.29-1.66) 1.97 (0.56-6.97) 0.4 3.02 (1.76-5.18)  8.57 (3.80-19.29) 0.85.65 (2.26-14.10) 17.49 (10.42-29.36) Geometric Mean (Lower- UpperGeometric 80% CI) Dose (mg) Cmax (ng/mL) AUC(0-tlqc) (ng · h/mL)Predicted Compound A Exposure 0.1 1.17 (0.66-2.05) 1.04 (0.67-1.62) 0.43.75 (2.54-5.54) 3.18 (1.98-5.12) 0.8 7.15 (4.85-10.54) 5.98 (3.60-9.91)Predicted M-II Exposure 0.1 0.69 (0.42-1.14) 1.97 (0.95-4.07) 0.4 3.02(2.13-4.27)  8.57 (5.09-14.41) 0.8 5.65 (3.34-9.55) 17.49 (13.0-23.55)

Experimental Example 8 Therapeutic Effectiveness on Maintenance(Maintenance of Remission Phase of Bipolar Disorder)

1. Test Tablet

The sublingual formulations of Example 8, Example 9 and Example 10

2. Test Method

The test tablet is administered sublingually to a patient at theremission phase of bipolar disorder once every night at bedtime for upto 9 months. Primary outcome can be measured according to the time fromrandomization to relapse events. The time from randomization to relapseover 9 months treatment period as determined by the Primary Investigator(PI) or defined by any of the following criteria: depression[Montgomery-Åsberg Depression Rating Scale (MADRS) score≧16];mania/hypomania [Young Mania Rating Scale (YMRS) total score≧14]; mixedepisode [MADRS score Z16 and YMRS total score≧14]; or, whetherparticipant receives psychiatric hospitalization for bipolar disorder,electroconvulsive therapy or any psychotropic medication changeprescribed for the treatment of depression, mania/hypomania or mixedepisodes.3. Test ResultCompound A is expected to be quite effective on maintenance therapy ofbipolar disorder at all doses.

Experimental Example 9 Therapeutic Effectiveness on Acute Depression (aDepression Symptom Associated with the Bipolar Disorder)

1. Test Tablet

The sublingual formulations of Example B, Example 9 and Example 10

2. Test Method

The test tablet is administered sublingually to a patient suffering frombipolar disorder once daily at night time for up to 8 weeks. Primaryoutcome can be measured according to change from baseline in theMontgomery-Åsberg Depression Rating Scale (MADRS) total score at week 8.MADRS is a 10-item clinician rated scale to measure overall severity ofdepressive symptoms (i.e., apparent sadness, reported sadness, innertension, etc.) rated on a 7-point Likert scale from 0 (normal) to 6(most abnormal) with a total score range from 0 to 60. Higher scoresindicate greater severity of symptoms.3. Test ResultCompound A is expected to be quite effective on acute depression at alldoses.

INDUSTRIAL APPLICABILITY

The present invention can provide a novel preparation showing improvedbioavailability of a medicament and a production method thereof and thelike.

When compound A is administered nasally (through nasal mucosa) to ahuman subject, it is expected to be effective on prophylaxis and/ortreatment of bipolar disease as administered oral-mucosally as disclosedabove. Compound A can be administered, for example, in the form of theformulation as disclosed in WO 01/15735.

When compound A is administered to a human subject, it can be alsoadministered in the dosage forms suitable for inhalation (e.g.nebulizer, etc) in order to prevent and/or treat bipolar disease. Thedosage forms can be produced according to a general production method inthis art. The dose of compound A can be decided referring to, forexample, the preparations (A) to (D) in the present application.

This application is based on patent application Nos. 2011-007371 and2011-227333 filed in Japan, international application No.PCT/JP2012/051279, and U.S. application Ser. Nos. 13/261,266 and13/491,887, the contents of which are incorporated in full herein.

The invention claimed is:
 1. A method for the treatment of a bipolardisorder comprising administering daily 0.05 to 1.0 mg of(S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide(compound A) to the oral mucosa of a human in need thereof, wherein theAUC ratio of a metabolite of compound A (M-II) to compound A in anunchanged form after administration is not more than
 20. 2. A method forthe treatment of a bipolar disorder comprising administering daily 0.1to 0.8 mg of(S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide(compound A) to the oral mucosa of a human in need thereof, wherein theAUC ratio of a metabolite of compound A (M-II) to compound A in anunchanged form after administration is not more than
 20. 3. The methodof claim 1, wherein the AUC ratio is not more than
 10. 4. The method ofclaim 2, wherein the AUC ratio is not more than
 10. 5. The methodaccording to claim 1, wherein the treatment of a bipolar disorder isselected from the group consisting of treatment of a depression symptomassociated with the bipolar disorder or maintenance of a remission phaseof the bipolar disorder.
 6. The method according to claim 5, wherein thedepression symptom associated with the bipolar disorder is acutedepression.
 7. The method according to claim 2, wherein the treatment ofa bipolar disorder is selected from the group consisting of treatment ofa depression symptom associated with the bipolar disorder or maintenanceof a remission phase of the bipolar disorder.
 8. The method according toclaim 7, wherein the depression symptom associated with the bipolardisorder is acute depression.
 9. The method according to claim 1,wherein the dosage of 0.05-1.0 mg is administered in one portion a day.10. The method according to claim 2, wherein the dosage of 0.1-0.8 mg isadministered in one portion a day.
 11. The method according to claim 1,comprising administering daily 0.1 to 0.8 mg of compound A.
 12. Themethod according to claim 1, wherein the dosage of 0.05-1.0 mg isadministered in one portion a day.
 13. The method according to claim 11,wherein the dosage of 0.1 to 0.8 mg is administered in one portion aday.